2,4-diaminopyrimidine compounds useful as immunosuppressants

ABSTRACT

Novel compounds according to the formula 
                 
         and pharmaceutically acceptable salts, solvates, or hydrates thereof; wherein   each occurrence of A is independently selected from CH or N;   X is selected from the group consisting of —CH 2 —, —O—, —NH—, (C 1 -C 6 )alkylamino-, (C 1 -C 6 )alkylaminocarbonylamino-, (C 1 -C 6 )alkylcarbonylamino-, (C 1 -C 6 )alkylsulfonylamino-, phenylsulfonylamino-, carbonyl, —NH—C(O)—, —N(C 1 -C 6 )alkyl-C(O)—, —S(O) y — where y is 0, 1 or 2, and;   n in —(CH 2 ) n — is 1, 2 or 3; and   R 1 , R 2 , and R 3  are as described herein; pharmaceutical compositions that including these compounds, and methods for the treatment of autoimmune disease, inflammation, allergy, transplant rejection, and other circumstances where administration of an immunosuppressive agent is of therapeutic benefit.

This application is a continuation of Ser. No. 10/116,554 filed Apr. 4,2002 now abandoned which is a continuation of Ser. No. 09/693,993 filedOct. 23, 2000 now abandoned which claims the benefit of ProvisionalApplication No. 60/168,224 filed Nov. 30, 1999.

FIELD OF THE INVENTION

The present invention relates to therapeutic modulation of T-cellmediated cellular processes. T-cells (“thymus-derived” cells) areresponsible for numerous cell-mediated immune functions, and indirectly,by stimulating B-cells, contribute to antibody production. The cellmembrane of a T-cell contains numerous receptor and accessory proteinmolecules that facilitate activation of T-cells, differentiation ofT-cells into various subtypes, and the interaction of T-cells with othercells or cell components.

Although T-cell mediated immune,responses are normally of great benefit,there are circumstances where it is appropriate to suppress or otherwisemodulate immune response mediated by activated T-cells. An importantexample is organ, tissue, or cell transplantation, where suppression ofimmune response against the transplant (whether allograft or xenograft)is essential. Additional examples include treatment of allergy,autoimmune disease, and disease states involving inflammation. SinceT-cells are involved in so many immune-mediated processes, and suchprocesses generally involve overlapping use of various T-cell proteinsand signaling functions, it has been very difficult to modulate onlycertain T-cell functions, without adversely affecting other desirablecellular processes. The present invention is directed to a class oftherapeutic compounds that selectively interfere with certain signalingevents that occur during T-cell activation, thus permitting selectiveregulation of immune response.

REPORTED DEVELOPMENTS

T-cells differentiate and proliferate in response to recognition ofantigens (generally, foreign macromolecules) in order to carry outvarious cell-mediated immune processes. This recognition of antigen,followed by functional and morphological changes in the T-cell, istermed activation. Among the functions carried out by differentiatedT-cells are (1) killing of virus-infected self cells, (2) killingforeign cells, (3) activation of other cells (for example, macrophages)that are capable of engulfing foreign particles (such as bacteria andviruses), and in turn processing their macromolecules for presentationto, and activation of, additional T-cells, (4) suppression of immuneresponse of B-cells and T-cells to antigen, which, for example, may actto establish immune tolerance, (5) activation of other T-cells, and (6)once themselves activated by antigen, helping B-cells respond to foreignantigens so that antibodies can be produced. In some cases these effectsare carried out by direct contact of T-cells with their targets, and inother cases T-cells secrete a variety of substances (generically termedlymphokines) in order to activate target cells at a distance, or bothmechanisms may be involved.

As aforementioned, autoimmune disease, transplant rejection, allergy,and inflammation represent disease states wherein undesired activationof antigen-specific T-cells appears necessary for induction and/orprogression of the unwanted clinical state. For example, necessaryrelease of some lymphokines (such as γ-interferon) by T-cells may causemacrophage cells to not only migrate to a site of infection or tissuedamage, but to release other soluble factors that slowly triggerundesired inflammation (for example, in delayed type hypersensitivity).Accordingly, pharmaceutical compounds that interrupt activation ofT-cells under specific circumstances, or specific downstream signallingevents, are expected to be of great therapeutic value. See, for example,J. H. Hanke, et al., Inflammation Research, 44, pp. 357-371, 1995.

T-cells recognize antigen through membrane glycoprotein receptors,called TcR, which are, in part, similar in structure and sequence to theantibodies of B-cells. The genetic elements from which the two proteinclasses are expressed are undoubtedly of common origin. In general,T-cells only recognize antigen that is presented to them, in processedform, on the surface of other cells. Like antibody producing B-cells,each individual progenitor T-cell only recognizes a particular aminoacid or carbohydrate sequence and/or other molecular structure (termedan epitope) in the processed antigen, which structure is usually uniqueto the antigen. Such specific recognition of antigen permits responseagainst a wide range of foreign macromolecules, and is a necessaryfeature of mechanisms whereby immune responses against self-moleculesare normally prevented.

Following the binding of antigen to the T-cell surface, numerous eventsmust occur in the cell membrane and inside the T-cell to complete itsactivation. As reviewed in Hanke et al., activation of the T-cellinvolves association of other cell membane glycoproteins, such as amongCD4, CD8, CD3 and CD28, with the TcR, and also phosphorylation oftyrosine amino acid residues in these proteins (see C. H. June et al.,Journal of Immunology, 144, pp. 1591-1599 (1990), and D. B. Strauss etal., Cell, 70, pp. 585-593, 1992). Phosphorylation of tyrosine aminoacid residues is carried out by a class of enzymes known as proteintyrosine kinases (PTKs). Inhibition of phosphorylation by tyrosinekinases has been shown to modulate T-cell activation, and numerousT-cell mediated immune processes. (see, for example, C. H. June et al.,Proceedings of the National Academy of Sciences, USA, 87, pp. 7722-7726,1990). Accordingly, regulation of T-cell activation (or subsequentsignal transducting events) by selective inhibition of particular PTKshas been of particular interest.

However, phosphorylation of tyrosine resides in membrane bound andcytoplasmic proteins is a general mechanism. It plays an important rolein numerous signaling pathways, not merely those confined to the immunesystem. Tyrosine phosphorylation occurs, for example, in response tobinding of growth factors such as epidermal growth factor (EGF),platelet-derived growth factor(PDGF), nerve growth factor (NGF), andalso insulin. Given the presence of a large number of cellular processesdependent upon tyrosine phosphorylation, it will be immediately apparentthat preferred compounds for inhibition of T-cell activation, and/orsubsequent immune system signalling events, should be designed toinhibit only one (or at most a very few) tyrosine kinases, to thus avoidinterfering with a wide range of other cellular metabolic pathways.

Additionally, since the specificity of a particular inhibitor compoundcannot be practically tested against all tyrosine kinases, and indeednumerous kinases remain to be discovered, it is most preferred toprovide compounds that are highly specific for a particular tyrosinekinase. A general discussion of tyrosine kinase proteins known to beassociated with T-cell activation is provided in J. H. Hanke et al.,1995. Tyrosine kinases (PTKs) involved in regulation of T-cellactivation include:

(a) Ick (a 56,000 MW protein, also known as p56^(Ick)) which isassociated with the TcR complex, and which is in the src-kinase family;

(b) fyn which is also in the src-kinase family;

(c) Zap-70 and syk, which share limited homology with src-kinases;

(d) itk kinase, which may be associated with the CD28 receptor; and

(e) csk-like kinases, and which may also negatively regulate thefunction of other PTKs.

Considerable evidence supports the involvement of Ick in T-cellactivation, and suggests that inhibition of Ick activity is an importantpoint of therapeutic intervention. D. B. Strauss et al., 1992,determined that mutant Jurkat cells (JcaM1) that failed to show anincrease in calcium levels following receptor stimulation lackedexpression of functional Ick tyrosine kinase. T. J. Molina et al.,Nature, 357, pp. 161-164, 1992 generated an Ick null mutation byhomologous recombination in murine embryonic stem cells. Lck-deficientmice evidenced pronounced thymic atrophy, and few CD4+, CD8+, orCD4+/CD8+ thymocytes were detected. Additionally, F. D. Goldman et al.,Journal of Clinical Investigation, 102, pp. 421-429, 1998, have reportedon an infant patient presenting a SCID (severe combined immunedeficiency) phenotype in which p59fyn and ZAP-70 kinases were expressedat normal levels, although a marked decrease in the level of Ick wasnoted. Interestingly, an alternatively spliced Ick transcript, thatlacked the kinase-encoding domain provided by exon 7 of the Ick gene,was identified from the patient.

There are reports in the scientific literature of compounds thatmodulate T-cell mediated immune function, and/or which inhibit tyrosinekinases (PTKs) of the receptor and non-receptor type. For example,published international patent documents WO 98/54156 and WO 98/54157describe quinoline and quinoxaline compounds that inhibitplatelet-derived growth factor PTK and/or Ick, and are useful inaffecting T-cell activation and proliferation. Additionally WO 97/40019discloses 5-aminopyrazole compounds useful as selective inhibitors ofIck. The disclosure in WO 98/11095 recites substituted2-pyrimidineamines, and their use as inhibitors of protein kinases suchas ZAP-70, protein kinase C and Ick. The compounds are described asuseful in regard to diseases or conditions involving the immune systemor cellular hyperproliferation. Additional publications of note includeWO 99/24035, WO 98/41525, WO 97/19065, WO 98/28281 and WO 98/18782.

The present invention provides pharmaceutical compounds useful for thetreatment of clinical conditions that involve inappropriate T-cellactivation. In particular, highly specific inhibitors of Ick tyrosinekinase are disclosed.

SUMMARY OF THE INVENTION

Accordingly, there are provided compounds according to the formula

or pharmaceutically acceptable salts, solvates, or hydrates thereof;wherein

each occurrence of A is independently selected from CH or N;

X is selected from the group consisting of —CH₂—, —O—, —NH—,(C₁-C₆)alkylamino-, (C₁-C₆)alkylaminocarbonylamino-,(C₁-C₆)alkylcarbonylamino-, (C₁-C₆)alkylsulfonylamino-,phenylsulfonylamino-, carbonyl, —NH—C(O)—, —N(C₁-C₆)alkyl-C(O)—,—S(O)_(y)— where y is 0, 1 or 2, and;

n in —(CH₂)_(n)— is 1, 2 or 3;

R¹ is selected from the groups consisting of (C₆-C₁₀)aryl-,(C₁-C₉)heteroaryl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl-,(C₆-C₁₀)aryl(C₁-C₉)heteroaryl-, (C₁-C₉)heteroaryl(C₁-C₉)heteroaryl-,(C₁-C₉)heteroaryl(C₆C₁₀)aryl-, (C₆-C₁₀)arylsulfinyl-,(C₆-C₁₀)aryl(C₆-C₁₀)arylsulfinyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylsulfinyl-, (C₆-C₁₀)arylsulfonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)arylsulfonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylsulfonyl-, (C₁-C₉)heteroarylsulfinyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylsulfinyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylsulfinyl-, (C₁-C₉)heteroarylsulfonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylsulfonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylsulfonyl-, (R⁴)sulfinyl-, (R⁴)sulfonyl-,(C₆-C₁₀)aryl(R⁴)sulfinyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryl(R⁴)sulfinyl-, (C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(R⁴)sulfinyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroaryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(R⁴)sulfonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroaryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryl(R⁴)sulfonyl-,(C₆-C₁₀)arylaminocarbonyl-, (C₆-C₁₀)aryl(C₆-C₁₀)arylaminocarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylaminocarbonyl-,(C₁-C₉)heteroarylaminocarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylaminocarbonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylaminocarbonyl-, (C₆-C₁₀)arylcarbonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)arylcarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylcarbonyl-, (C₁-C₉)heteroarylcarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylcarbonyl-(C₁-C₉)heteroaryl(C₁-C₉)heteroarylcarbonyl-,(C₆-C₁₀)aryloxycarbonyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryloxycarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryloxycarbonyl-,(C₁-C₉)heteroaryloxycarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroaryloxycarbonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryloxycarbonyl-, (R⁴)carbonyl-,(R⁴)oxycarbonyl-, (R⁴)aminocarbonyl-, (C₆-C₁₀)aryl(R⁴)carbonyl-,(C₆-C₁₀)aryl(R⁴)oxycarbonyl-, (C₆-C₁₀)aryl(R⁴)aminocarbonyl-,(C₁-C₉)heteroaryl(R⁴)carbonyl-, (C₁-C₉)heteroaryl(R⁴)oxycarbonyl-, and(C₁-C₉)heteroaryl(R⁴)aminocarbonyl-;

wherein R⁴ is selected from the groups consisting of

(a) (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, or (C₂-C₆)alkynyl-, wherein thealkyl-, alkenyl- and alkynyl- groups are optionally substituted byhydroxy, halo, amino, trifluoromethyl, hydroxy(C₂-C₆)alkyl-,(C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-,((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano, nitro, (C₁-C₆)alkyl-,(C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, or nitro(C₁-C₆)alkyl-;

(b) (C₃-C₁₀)cycloalkyl-, wherein the cycloalkyl- group is optionallysubstituted by hydroxy, halo, amino, trifluoromethyl,hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-,(C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano,nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-, trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, or nitro(C₁-C₆)alkyl-; or

(c) (C₃-C₁₀)heterocycloalkyl-, wherein the heterocycloalkyl- group isoptionally substituted by hydroxy, halo, amino, trifluoromethyl,hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-,(C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano,nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-, trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, or nitro(C₁-C₆)alkyl-; and

wherein any of said of (C₆-C₁₀)aryl- or (C₁-C₉)heteroaryl- groups of R¹may be optionally substituted by one to five groups selected from

(a) deuterium, hydroxy, halo, amino, trifluoromethyl, carboxy,(C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-,((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano, nitro, (C₁-C₆)alkyl-,(C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-, or nitro(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acylamino-,amino(C₁-C₆)acyl-, amino(C₁-C₆)acyl(C₁-C₆)alkyl-,(C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-, (C₁-C₆)acyloxy(C₁-C₆)alkyl-,(C₂-C₆)alkoxy(C₁-C₆)alkyl-, piperazinyl(C₁-C₆)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₅-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-,(C₁-C₆)alkyl(difluoromethylene)-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acyl-,(C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-,(C₆-C₁₀)aryl-, (C₁-C₉)heteroaryl-, (C₆-C₁₀)aryl(C₁-C₆)alkyl-,(C₁-C₉)heteroaryl(C₁-C₆)alkyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl-, (C₃-C₁₀)cycloalkyl-,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl-, (C₃-C₁₀)heterocycloalkyl-,(C₃-C₁₀)heterocycloalkyl(C₁-C₆)alkyl-, hydroxy(C₂-C₆)alkyl-,(C₁-C₆)acyloxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy(C₂-C₆)alkyl-,piperazinyl(C₁-C₆)alkyl-, (C₁-C₆)acylamino(C₁-C₆)alkyl-,(C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl-;

(b) R⁵OCO(C₁-C₆)alkyl-, wherein R⁵ is selected from the group consistingof hydrogen, (C₁C₆)alkyl-, (C₆-C₁₀)aryl(C₁-C₆)alkyl-,(C₁-C₉)heteroaryl(C₁-C₆)alkyl-; or

(c) R⁶(C₀-C₆)alkyl-, wherein R⁶ is selected from the group consisting ofpiperazino, (C₁-C₆)acylpiperazino-, (C₆-C₁₀)arylpiperazino-,(C₅-C₉)heteroarylpiperazino-, (C₁-C₆)alkylpiperazino-,(C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpiperazino-, morpholino-,(C₁-C₆)acylmorpholino-, (C₆-C₁₀)arylmorpholino-,(C₁-C₉)heteroarylmorpholino-, (C₁-C₆)alkylmorpholino-,(C₆-C₁₀)aryl(C₁-C₆)alkylmorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylmorpholino-, thiomorpholino-,(C₁-C₆)acylthiomorpholino-, (C₆-C₁₀)arylthiomorpholino-,(C₁-C₉)heteroarylthiomorpholino-, (C₁-C₆)alkylthiomorpholino-,(C₆-C₁₀)aryl(C₁-C₆)alkylthiomorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiomorpholino-, piperidino-,(C₁-C₆)acylpiperidino-, (C₆-C₁₀)arylpiperidino-,(C₁-C₉)heteroarylpiperidino-, (C₁-C₆)alkyl piperidino-,(C₆-C₁₀)aryl(C₁-C₆)piperidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpiperidino-, pyrrolidino-,(C₁-C₆)acylpyrrolidino-, (C₆-C₁₀)aryl-pyrrolidino-,(C₁-C₉)heteroaryl-pyrrolidino-, (C₁-C₆)alkylpyrrolidino-,(C₆-C₁₀)aryl(C₁-C₆)pyrrolidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpyrrolidino-, (C₁-C₆)alkoxy(C₁-C₆)acyl-,(C₁-C₆)alkylamino(C₆-C₁₀)aryl-, and ((C₁-C₆)alkyl₂amino(C₁-C₆)acyl-;

R² represents one to four optional substituents, each beingindependently selected from the members of groups (a) to (f)

(a) deuterium, halo, hydroxy, carboxy, amino, trifluoromethyl,(C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂C₆)alkynyl-, (C₁-C₆)alkylamino-,((C₁-C₆)(alkyl)₂amino-, cyanoalkyl-, (C₃-C₁₀)cycloalkyl-,(C₃-C₁₀)heterocycloalkyl-, (C₃-C₁₀)cycloalkoxy-, (C₁-C₆)alkylthio-,(C₁-C₆)alkylsulfinyl-, (C₁-C₆)alkylsulfonyl-, amino-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl-, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkoxy-,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy-, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy-,(C₁-C₆)alkylamino-CO—NH—, (C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl-,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl-,((C₁-C₆)alkyl)₂amino-CO—NH-carboxy, carboxy(C₁-C₆)alkyl-,carboxy(C₁-C₆)alkoxy-, benzyloxycarbonyl(C₁-C₆)alkoxy-,(C₁-C₆)alkylamino-CO—, (C₁-C₆)acylamino-, (C₁-C₆)alkoxy-, (C₁-C₆)acyl-,(C₁-C₆)acyloxy-, (C₁-C₆)acyl(C₁-C₆)alkylamino-, (C₁-C₆)alkoxyacyl-,(C₁-C₆)alkylaminoacyl-, ((C₁-C₆)alkyl)₂aminoacyl-, amino(C₁-C₆)acyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkoxycarbonylamino-,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl-,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino-, trihalomethyl-,trihalomethyl(C₁-C₆)alkyl-, (C₁-C₆)alkyldihalomethylene-,(C₁-C₃)alkyl(dihalomethylene)(C₁-C₃)alkyl-, (C₃-C₆)cycloalkyl-,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl-, hydroxy(C₁-C₆)alkyl-,(C₁-C₆)acyloxy(C₁-C₆)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₁-C₆)alkylthio(C₁-C₆)alkyl-,(C₁-C₆)alkoxycarbonyl-, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₁-C₆)alkylsulfonyl-,(C₁-C₆)alkylsulfonylamino-, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl-, (C₁-C₆)CO(C₁-C₆)alkyl-;

(b) (C₆-C₁₀)aryl-, (C₁-C₉)heteroaryl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl-,(C₆-C₁₀)aryl(C₁-C₉)heteroaryl-, (C₁-C₉)heteroaryl(C₁-C₉)heteroaryl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryl-, (C₆-C₁₀)arylsulfinyl-,(C₆-C₁₀)aryl(C₆-C₁₀)arylsulfinyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylsulfinyl-, (C₆-C₁₀)arylsulfonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)arylsulfonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylsulfonyl-, (C₁-C₉)heteroarylsulfinyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylsulfinyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylsulfinyl-, (C₁-C₉)heteroarylsulfonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylsulfonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylsulfonyl-, (R⁴)sulfinyl-, (R⁴)sulfonyl-,(C₆-C₁₀)aryl(R⁴)sulfinyl-, (C₆-C₁₀)aryl(R⁴)sulfinyl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryl(R⁴)sulfinyl-, (C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(R⁴)sulfinyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroaryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(R⁴)sulfonyl-,(C₆-C₁₀)aryl(C₅-C₉)heteroaryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryl(R⁴)sulfonyl-,(C₆-C₁₀)arylaminocarbonyl-, (C₆-C₁₀)aryl(C₆-C₁₀)arylaminocarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylaminocarbonyl-,(C₁-C₉)heteroarylaminocarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylaminocarbonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylaminocarbonyl-, (C₆-C₁₀)arylcarbonyl-,(C₈-C₁₀)aryl(C₈-C₁₀)arylcarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylcarbonyl-, (C₁-C₉)heteroarylcarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylcarbonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylcarbonyl-, (C₆-C₁₀)aryloxycarbonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryloxycarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryloxycarbonyl-,(C₁-C₉)heteroaryloxycarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroaryloxycarbonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryloxycarbonyl-, (R⁴)carbonyl-,(R⁴)oxycarbonyl-, (R⁴)aminocarbonyl-, (C₆-C₁₀)aryl(R⁴)carbonyl-,(C₆-C₁₀)aryl(R⁴)oxycarbonyl-, (C₆-C₁₀)aryl(R⁴)aminocarbonyl-,(C₁-C₉)heteroaryl(R⁴)carbonyl-, (C₅-C₉)heteroaryl(R⁴)oxycarbonyl-,(C₁-C₉)heteroaryl(R⁴)aminocarbonyl-, wherein R⁴ is defined as above, andwherein any of said of (C₆-C₁₀)aryl- or (C₁-C₉)heteroaryl-R² groups maybe optionally substituted by one to five groups independently selectedfrom:

-   -   (i) hydroxy, halo, amino, trifluoromethyl, carboxy,        (C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-,        ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano, nitro,        (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,        (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,        trifluoromethyl(C₁-C₆)alkyl-, or nitro(C₁-C₆)alkyl-,        (C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-,        (C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acylamino-,        amino(C₁-C₆)acyl-, amino(C₁-C₆)acyl(C₁-C₆)alkyl-,        (C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-,        (C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-, (C₁-C₆)acyloxy(C₁-C₆)alkyl-,        (C₂-C₆)alkoxy(C₁-C₆)alkyl-, piperazinyl(C₁-C₆)alkyl-,        (C₁-C₆)acylamino(C₁-C₆)alkyl-,        (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,        (C₁-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,        (C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,        (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-,        (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,        (C₁-C₅)alkylsulfonyl(C₁-C₆)alkyl-,        (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-, amino(C₁-C₆)alkyl-,        (C₁-C₆)alkylamino(C₁-C₆)alkyl-,        (C₁-C₆)alkyl(difluoromethylene)-,        (C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-,        (C₁-C₆)alkoxy(C₁-C₆)acyl-, (C₁-C₆)alkylamino(C₁-C₆)acyl-,        ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-, (C₆-C₁₀)aryl-,        (C₁-C₉)heteroaryl-, (C₆-C₁₀)aryl(C₁-C₆)alkyl-,        (C₁-C₉)heteroaryl(C₁-C₆)alkyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl-,        (C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl-, (C₃-C₁₀)cycloalkyl-,        (C₃-C₆)cycloalkyl(C₁-C₆)alkyl-, (C₃-C₁₀)heterocycloalkyl-,        (C₃-C₁₀)heterocycloalkyl(C₁-C₆)alkyl-, hydroxy(C₂-C₆)alkyl-,        (C₁-C₆)acyloxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy(C₂-C₆)alkyl-,        piperazinyl(C₁-C₆)alkyl-, (C₁-C₆)acylamino(C₁-C₆)alkyl-,        (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,        (C₁-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,        (C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,        (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-,        (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,        (C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-,        (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-, amino(C₁-C₆)alkyl-,        (C₁-C₆)alkylamino(C₁-C₆)alkyl-,        ((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl-;    -   (ii) R⁵OCO(C₁-C₆)alkyl—wherein R⁵ is selected from the group        consisting of hydrogen, (C₁-C₆)alkyl, (C₆-C₁₀)aryl(C₁-C₆)alkyl-,        (C₁-C₉)heteroaryl(C₁-C₆)alkyl-;    -   (iii) R⁶(C₂-C₆)alkyl—wherein R⁶ is selected from the group        consisting of piperazino, (C₁-C₆)acylpiperazino-,        (C₆-C₁₀)arylpiperazino-, (C₅-C₉)heteroarylpiperazino-,        (C₁-C₆)alkylpiperazino-, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino-,        (C₁-C₉)heteroaryl(C₁-C₆)alkylpiperazino-, morpholino-,        (C₁-C₆)acylmorpholino-, (C₆-C₁₀)arylmorpholino-,        (C₁-C₉)heteroarylmorpholino-, (C₁-C₆)alkylmorpholino-,        (C₆-C₁₀)aryl(C₁-C₆)alkylmorpholino-,        (C₁-C₉)heteroaryl(C₁-C₆)alkylmorpholino-, thiomorpholino-,        (C₁-C₆)acylthiomorpholino-, (C₆-C₁₀)arylthiomorpholino-,        (C₁-C₉)heteroarylthiomorpholino-, (C₁-C₆)alkylthiomorpholino-,        (C₆-C₁₀)aryl(C₁-C₆)alkylthiomorpholino-,        (C₁-C₉)heteroaryl(C₁-C₆)alkylthiomorpholino-, piperidino-,        (C₁-C₆)acylpiperidino-, (C₆-C₁₀)arylpiperidino-,        (C₁-C₉)heteroarylpiperidino-, (C₁-C₆)alkyl piperidino-,        (C₆-C₁₀)aryl(C₁-C₆)piperidino-,        (C₁-C₉)heteroaryl(C₁-C₆)alkylpiperidino-, pyrrolidino-,        (C₁-C₆)acylpyrrolidino-, (C₆-C₁₀)arylpyrrolidino-,        (C₁-C₉)heteroarylpyrrolidino, (C₁-C₆)alkylpyrrolidino-,        (C₆-C₁₀)aryl(C₁-C₆)alkylpyrrolidino-,        (C₁-C₉)heteroaryl(C₁-C₆)alkylpyrrolidino-,        (C₁-C₆)alkoxy(C₁-C₆)acyl-, (C₁-C₆)alkylamino(C₆-C₁₀)aryl-, and        ((C₁-C₆)alkyl₂amino(C₁-C₆)acyl-;

(c) R⁷, or R⁷Y-, where R⁷ is selected from the group consisting ofpiperazino-, (C₆-C₁₀)arylpiperazino-, (C₁-C₉)heteroarylpiperazino-,(C₁-C₆)alkylpiperazino-, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpiperazino-, morpholino-,(C₆-C₁₀)arylmorpholino-, (C₁-C₉)heteroarylmorpholino-,(C₁-C₆)alkylmorpholino-, (C₆-C₁₀)aryl(C₁-C₆)alkylmorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylmorpholino-, thiomorpholino-,(C₆-C₁₀)arylthiomorpholino-, (C₁-C₉)heteroarylthiomorpholino-,(C₁-C₆)alkylthiomorpholino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiomorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiomorpholino-, piperidino-,(C₆-C₁₀)arylthiopiperidino-, (C₁-C₉)heteroarylthiopiperidino-,(C₁-C₆)alkylthiopiperidino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiopiperidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiopiperidino-, pyrolidino-,(C₆-C₁₀)arylthiopyrolidino-, (C₁-C₉)heteroarylthiopyrolidino-,(C₁-C₆)alkylthiopyrolidino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiopyrolidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiopyrolidino-, and Y, if present, isselected from the group consisting of (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-,(C₂-C₆)alkynyl-, amino, oxygen, thio, sulfinyl, sulfonyl,halo(C₁-C₆)alkyl-, and hydroxy(C₂-C₆)alkyl-;

(d) ZR⁸—, where R⁸ is selected from the group consisting of piperazino-,(C₆-C₁₀)arylpiperazino-, (C₁-C₉)heteroarylpiperazino-,(C₁-C₆)alkylpiperazino-, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpiperazino-, morpholino-,(C₆-C₁₀)arylmorpholino-, (C₁-C₉)heteroarylmorpholino-,(C₁-C₆)alkylmorpholino-, (C₆-C₁₀)aryl(C₁-C₆)alkylmorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylmorpholino-, thiomorpholino-,(C₆-C₁₀)arylthiomorpholino-, (C₁-C₉)heteroarylthiomorpholino-,(C₁-C₆)alkylthiomorpholino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiomorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiomorpholino-, piperidino-,(C₆-C₁₀)arylthiopiperidino-, (C₁-C₉)heteroarylthiopiperidino-,(C₁-C₆)alkylthiopiperidino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiopiperidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiopiperidino-, pyrolidino-,(C₆-C₁₀)arylthiopyrolidino-, (C₁-C₉)heteroarylthiopyrolidino-,(C₁-C₆)alkylthiopyrolidino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiopyrolidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiopyrolidino-, and Z is selected from thegroup consisting of (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,amino, oxygen, thio, sulfinyl, sulfonyl, halo(C₁-C₆)alkyl-, andhydroxy(C₂-C₆)alkyl-;

(e) two or more of R², when vicinal, together to form one or morefurther rings of 4, 5, 6 or 7 member atoms selected from the groupconsisting of phenyl-, naphthyl-, furyl-, thienyl-, thiazolyl-,pyrazolyl-, isothiazolyl-, oxazolyl-, isoxazolyl-, pyrrolyl-,triazolyl-, tetrazolyl-, imidazolyl-, 1,3,5-oxadiazolyl-,1,2,4-oxadiazolyl-, 1,2,3-oxadiazolyl-,1,3,5-thiadiazolyl,-1,2,3-thiadiazolyl-, 1,2,4-thiadiazolyl-, pyridyl-,pyrimidyl-, pyrazinyl-, pyridazinyl-, 1,2,4-triazinyl-,1,2,3-triazinyl-, 1,3,5-triazinyl-, pyrazolo[3,4-b]pyridinyl-,cinnolinyl-, pteridinyl-, purinyl-, 6,7-dihydro-5H-[1]pyrindinyl-,benzo[b]thiophenyl-, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl-,benzothiazolyl-, benzisothiazolyl-, benzisoxazolyl-, benzimidazolyl-,thianaphthenyl-, isothianaphthenyl-, benzofuranyl-, isobenzofuranyl-,isoindolyl-, indolyl-, indolizinyl-, indazolyl-, isoquinolyl-,quinolyl-, phthalazinyl-, quinoxalinyl-, quinazolinyl-, benzoxazinyl-,and wherein said ring(s) are optionally substituted by one or more(C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, amino-, halo-,hydroxy-, carboxy-, thiol-, nitro-, cyano-, sulfonic-,halo(C₁-C₆)alkyl-, and hydroxy(C₂-C₆)alkyl-; and

(f) two or more of R² when vicinal, together to form one or more furtherrings of 3, 4, 5, 6 or 7 member atoms selected from the groupsconsisting of:

-   -   (i) (C₃-C₁₀)cycloalkyl-, containing zero to two levels of        unsaturation, selected from the group consisting of        cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-,        cycloheptyl-, cyclopropenyl-, cyclobutenyl-, cyclopentenyl-,        cyclohexenyl-, cycloheptenyl-, 1,3-cyclobutadienyl-,        1,3-cyclopentadienyl-, 1,3-cyclohexadienyl-,        1,4-cyclohexadienyl-, 1,3-cycloheptadienyl-,        1,4-cycloheptadienyl-, bicyclo[3.2.1]octane-,        bicyclo[2.2.1]heptane, the norborn-2-ene unsaturated form        thereof, and the like, wherein said ring is optionally        substituted by hydroxy-, halo-, amino-, trifluoromethyl-,        hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-,        (C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-,        cyano-, nitro-, carboxy-, thiol-, sulfonyl-, (C₁-C₆)alkyl-,        (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, (C₁-C₆)acylamino-,        cyano(C₁-C₆)alkyl-, trifluoromethyl(C₁-C₆)alkyl-,        (C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, halo(C₁-C₆)alkyl-        or nitro(C₁-C₆)alkyl-; and    -   (ii) (C₃-C₁₀)heterocycloalkyl- selected from the group        consisting of pyrrolidinyl-, tetrahydrofuranyl-,        dihydrofuranyl-, tetrahydropyranyl-, pyranyl-, thiopyrany-l,        aziridinyl-, oxiranyl-, methylenedioxyl-,        isoxazolidinyl,-1,3-oxazolidin-3-yl-, isothiazolidinyl-,        1,3-thiazolidin-3-yl-, 1,2-pyrazolidin-2-yl-,        1,3-pyrazolidin-1-yl-, piperidinyl-, thiomorpholinyl-,        1,2-tetrahydrothiazin-2-yl-, 1,3-tetrahydrothiazin-3-yl-,        tetrahydrothiadiazinyl-, morpholinyl-,        1,2-tetrahydrodiazin-2-yl-, 1,3-tetrahydrodiazin-1-yl-,        tetrahydroazepinyl-, piperazinyl-, chromenyl-, chromanyl-, where        said ring is optionally substituted by hydroxy-, halo-, amino-,        trifluoromethyl-, hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-,        (C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-,        (C₁-C₆)acylamino-, cyano-, nitro-, carboxy-, thiol-, sulfonyl-,        (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,        (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,        trifluoromethyl(C₁-C₆)alkyl-,        (C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, halo(C₁-C₆)alkyl-        or nitro(C₁-C₆)alkyl-;

wherein any (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₃-C₁₀)cycloalkyl- or (C₃-C₁₀)heterocycloalkyl- groups that are, orcomprise a portion of, said one to four optional R² substituents arethemselves optionally substituted by deuterium-, hydroxy-, amino-,trifluoromethyl-, cyano-, nitro-, carboxy-, (C₁-C₄)alkoxy-,(C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-,(C₁-C₆)alkyl-(C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, (C₁-C₆)acylamino-,(C₃-C₁₀)cycloalkyl-, (C₃-C₁₀)heterocycloalkyl-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-, nitro(C₁-C₆)alkyl-, and (C₁-C₆)acylamino;and.

R³ represents one or more optional substituents on a ring carbon atom,including at X where X is —CH₂—, selected from the groups consisting of(C₁-C₆)alkyl-, trihalo(C₁-C₆)alkyl- that is preferably trifluoromethyl-,deuterium, and fluorine.

According to the practice of the invention, with respect to thestructural component of compounds of formula I that is represented by

preferred examples include those where the ring structure is contributedby 1,2,3,4-tetrahydroquinoline; 1,2,3,4-tetrahydroquinoxaline;3,4-dihydro-1H-quinoxaline-2-one (also named2-oxo-1,2,3,4-tetrahydroquinoxaline); 3,4-dihydro-2H-benzo[1,4]oxazine;2,3-dihydro-1H-indole; and 3,4-dihydro-2H-benzo[1,4]thiazine,respectively, as depicted below.

Preferred examples of the above six structures include6-methoxy-1,2,3,4-tetrahydroquinoline;4-methyl-1,2,3,4-tetrahydroquinoline;7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline;8-methyl-1,2,3,4-tetrahydroquinoline,6-hydroxy-1,2,3,4-tetrahydroquinoline;8-chloro-1,2,3,4-tetrahydroquinoline,7-chloro-1,2,3,4-tetrahydroquinoline;6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroquinoline;6,7-dimethyl-1,2,3,4-tetrahydroquinoxaline;1,2,3,4-tetrahydroquinoxaline;1-phenylsulfonyl-1,2,3,4-tetrahydroquinoxaline;6-Methyl-1,2,3,4-tetrahydroquinoline; 3,4-dihydro-2H-benzo[1,4]oxazine;5-Fluoro-2,3-dihydro-1H-indole; 1,2,3,4-tetrahydroquinoxaline; and3,3-dimethyl-2,3-dihydro-1H-indole.

In additional embodiments of the invention, the

structure is defined, for example, by2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine;2,3-Dihydro-1H-pyrrolo[2,3-c]pyridine;2,3-Dihydro-1H-pyrrolo[3,2-c]pyridine;2,3-Dihydro-1H-pyrrolo[3,2-b]pyridine;6,7-Dihydro-5H-pyrrolo[3,2-d]pyrimidine;6,7-Dihydro-5H-pyrrolo[3,2-d][1,2,3]triazine;6,7-Dihydro-5H-pyrrolo[2,3-d][1,2,3]triazine; 1,4,5,7-Tetraaza-indan;1,4,6,7-Tetraaza-indan; 6,7-Dihydro-5H-pyrrolo[2,3-c]pyridazine;2,3-Dihydro-1H-pyrrolo[2,3-d]pyridazine;6,7-Dihydro-5H-pyrrolo[3,2-c]pyridazine;6,7-Dihydro-5H-pyrrolo[2,3-b]pyrazine;6,7-Dihydro-5H-pyrimido[4,5-b][1,4]oxazine;5,6,7,8-Tetrahydro-pteridine; 1,2,3,4-Tetrahydro-pyrido[2,3-b]pyrazine;1,2,3,4-Tetrahydro-pyrido[3,4-b]pyrazine;1,2,3,4-Tetrahydro-pyrido[3,4-b]pyrazine;1,2,3,4-Tetrahydro-pyrido[2,3-b]pyrazine;5,6,7,8-Tetrahydro-pyrazino[2,3-c]pyridazine;5,6,7,8-Tetrahydro-pteridine;1,2,3,4-Tetrahydro-pyrazino[2,3-d]pyridazine;5,6,7,8-Tetrahydro-pyrazino[2,3-c]pyridazine;1,2,3,4-Tetrahydro-pyrazino[2,3-b]pyrazine;5,6,7,8-Tetrahydro-pyrazino[2,3-e][1,2,4]triazine;5,6,7,8-Tetrahydro-pyrazino[2,3-e][1,2,4]triazine;5,6,7,8-Tetrahydro-pyrazino[2,3-d][1,2,3]triazine;5,6,7,8-Tetrahydro-pyrazino[2,3-d][1,2,3]triazine;2,3-Dihydro-1H-4-oxa-1,5-diaza-naphthalene;2,3-Dihydro-1H-4-oxa-1,6-diaza-naphthalene;3,4-Dihydro-2H-1-oxa-4,6-diaza-naphthalene;3,4-Dihydro-2H-1-oxa-4,5-diaza-naphthalene;7,8-Dihydro-6H-5-oxa-1,2,8-triaza-naphthalene;3,4-Dihydro-2H-1-oxa-4,6,7-triaza-naphthalene;6,7-Dihydro-5H-8-oxa-1,2,5-triaza-naphthalene;3,4-Dihydro-2H-1-oxa-4,5,8-triaza-naphthalene;7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazine;6,7-Dihydro-5H-pyrimido[4,5-b][1,4]oxazine;6,7-Dihydro-5H-8-oxa-1,2,3,5-tetraaza-naphthalene;6,7-Dihydro-5H-8-oxa-1,2,4,5-tetraaza-naphthalene;7,8-Dihydro-6H-5-oxa-1,2,3,8-tetraaza-naphthalene;6,7-Dihydro-5H-8-oxa-1,2,4,5-tetraaza-naphthalene;2,3-Dihydro-1H-pyrido[2,3-b][1,4]thiazine;2,3-Dihydro-1H-4-thia-1,6-diaza-naphthalene;3,4-Dihydro-2H-1-thia-4,6-diaza-naphthalene;3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazine;7,8-Dihydro-6H-5-thia-1,2,8-triaza-naphthale;3,4-Dihydro-2H-1-thia-4,6,7-triaza-naphthalene;6,7-Dihydro-5H-8-thia-1,2,5-triaza-naphthalene;6,7-Dihydro-5H-pyrimido[4,5-b][1,4]thiazine;7,8-Dihydro-6H-pyrimido[5,4-b][1,4]thiazine;3,4-Dihydro-2H-1-thia-4,5,8-triaza-naphthalene;6,7-Dihydro-5H-8-thia-1,2,4,5-tetraaza-naphthalene;7,8-Dihydro-6H-5-thia-1,2,4,8-tetraaza-naphthalene;7,8-Dihydro-6H-5-thia-1,2,3,8-tetraaza-naphthalene;6,7-Dihydro-5H-8-thia-1,2,3,5-tetraaza-naphthalene;5,6,7,8-Tetrahydro-pyrido[3,2-d]pyrimidine;1,2,3,4-Tetrahydro-pyrido[2,3-d]pyridazine;5,6,7,8-Tetrahydro-pyrido[2,3-b]pyrazine;5,6,7,8-Tetrahydro-pyrido[3,2-e][1,2,4]triazine;5,6,7,8-Tetrahydro-pyrido[2,3-e][1,2,4]triazine;5,6,7,8-Tetrahydro-pyrido[3,2-d][1,2,3]triazine; and5,6,7,8-Tetrahydro-pyrido[2,3-d][1,2,3]triazine.

It is additionally preferred that one or more of substituents R² beselected from the groups consisting of:

(a) (C₁-C₆)alkyl-, (C₁-C₆)alkynl-, (C₁-C₆)alkoxy-, trihalo(C₁-C₆)alkyl-that is preferably trifluoromethyl-, (C₁-C₆)alkylamino-,((C₁-C₆)₂)dialkylamino-, amino-, cyano, and halo-; and

(b) benzyloxy-, phenylsulfonyl-, phenylaminocarbonyl-,(C₁-C₉)heteroarylsulfonyl-, and (C₁-C₉)heteroarylaminocarbonyl-,optionally substituted by one or more groups selected from the groupconsisting of (C₁-C₆)alkyl-, (C₂-C₆)alkynyl-, trihalo(C₁-C₆)alkyl—thatis preferably trifluoromethyl-, (C₁-C₆)alkoxy-, (C₁-C₆)alkylamino-,((C₁-C₆)₂)alkylamino-, and halo.

According to the practice of the invention, preferred examples of R¹include (C₆-C₁₀)aryl-, and (C₁-C₉) heteroaryl—wherein said R¹ group isoptionally substituted by one or more groups, each independentlyselected from hydroxy, halo, amino, (C₁-C₆)alkyl-, (C₁-C₆)alkoxy-,trihalo(C₁-C₆)alkyl—that is preferably trifluoromethyl-, (C₁-C₆)alkynl-,(C₁-C₆)alkylamino-, ((C₁-C₆)₂)dialkylamino-, carboxy-,(C₁-C₆)alkoxycarbonyl-, (C₁-C₆)acyloxy-,and (C₁-C₆)acylamino-.

In a preferred embodiment of the invention, R¹ is a (C₁-C₉)heteroaryl-group selected from the group consisting of pyridyl-, indazolyl-,indolyl-, 1,3-dihydro-benzoimidazol-2-one, thienyl-, oxazoyl-,2H-pyrazolyl-, 1H-pyrazolyl-, isooxazoyl-, thiazolyl(fix,name), andisothiazoyl-, and is optionally substituted by one or more groups, eachindependently selected from hydroxy-, halo-, amino-, (C₁-C₆)alkyl-,(C₁-C₆)alkoxy-, trihalo(C₁-C₆)alkyl- that is preferablytrifluoromethyl-, (C₁-C₆)alkynl-, (C₁-C₆)alkylamino-,((C₁-C₆)₂)dialkylamino-, carboxy-, (C₁-C₆)alkoxycarbonyl-,(C₁-C₆)acyloxy-, and (C₁-C₆)acylamino-.

In an additionally preferred embodiment of the invention, R¹ is phenyl,optionally substituted with one to five substituents, that are eachindependently selected from hydroxy-, halo-, amino-, (C₁-C₆)alkyl-,(C₁-C₆)alkoxy-, trihalo(C₁-C₆)alkyl- that is preferablytrifluoromethyl-, (C₁-C₆)alkynl-, (C₁-C₆)alkylamino-,((C₁-C₆)₂)dialkylamino-, carboxy, (C₁-C₆)alkoxycarbonyl-,(C₁-C₆)acyloxy-, and (C₁-C₆)acylamino-.

Particularly preferred examples of R¹ include 3,4,5-trimethoxyphenyl-;2,3-dimethyl-1H-indol-5-yl; 3,4-dihydro-2H-quinolin-1-yl; and6-morpholin-4-yl-pyridin-3-yl.

Representative compounds of the invention include:

(a) 1-[(2-anilino)-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;

(b)1-[2-[(4-bromophenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;

(c)1-[2-[(4-methoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;

(d)1-[2-[(1H-indazole-5-yl)]-4-pyrimidyl]-6-methyl-1,2,3,4-tetrahydroquinoline;

(e)1-[2-[(4-phenoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;

(f)1-[2-[(3,4-dimethoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;

(g)1-[2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;

(h)1-[2-[(4,N-phenylaminophenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;

(i)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-amine;

(j)5-[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-1,3-dihydro-benzoimidazol-2-one;

(k)(2,3-Dimethyl-1H-indol-5-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;

(l)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(2-methyl-2H-pyrazol-3-yl)-amine;

(m)(6-Methoxy-pyridin-3-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;

(n)(4-Fluoro-3-methyl-phenyl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;

(o)(5-Cyclopropyl-2H-pyrazol-3-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;

(p)4-Benzyl-N3-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-1H-pyrazole-3,5-diamine;

(q)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(4-methyl-thiazol-2-yl)-amine;and

(r)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(5-methyl-1H-pyrazol-3-yl)-amine.

Additional preferred compounds of the invention include[4-(3,4-Dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(6-pyrrolidin-1-yl-pyridin-3-yl)-amine;(1-Cyclopentyl-1H-indol-6-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-oxazol-4-yl-amine;(3,4-Dichloro-phenyl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;and[4-(3,4-Dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-isothiazol-3-yl-amine.

Additional preferred compounds of the invention include:

2-({5-[4-(2,3-Dihydro-benzo[1,4]oxazin-4-yl)-pyrimidin-2-ylamino]-pyridin-2-yl}-methyl-amino)-ethanol;

N-{5-[4-(3-Oxo-3,4-dihydro-2H-quinoxalin-1-yl)-pyrimidin-2-ylamino]-pyridin-2-yl}-acetamide;

3-Chloro-N-[4-(4-methyl-3-oxo-3,4-dihydro-2H-quinoxalin-1-yl)-pyrimidin-2-yl]-benzamide;

[4-(2,3-Dihydro-benzo[1,4]thiazin-4-yl)-pyrimidin-2-yl]-oxazol-4-yl-amine;

N-[4-(5-Fluoro-2,3-dihydro-indol-1-yl)-pyrimidin-2-yl]-3-methoxy-benzenesulfonamide;

[4-(5,6-Dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyrimidin-2-yl]-(2-trifluoromethyl-phenyl)-amine;

6-Methoxy-1-[2-(pyridazin-3-ylamino)-pyrimidin-4-yl]-2,3-dihydro-1H-quinolin-4-one;

2-{5-[4-(3,4-Dihydro-2H-quinoxalin-1-yl)-pyrimidin-2-ylamino]-indol-1-yl}-ethanol;

(2H-Pyrazol-3-yl)-[4-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;

1-[4-(3,4-Dihydro-2H-[1,5]naphthyridin-1-yl)-pyrimidin-2-yl]-3-ethyl-urea;

1-[4-(2,3-Dihydro-benzo[1,4]oxazin-4-yl)-pyrimidin-2-yl]-3-(2-ethoxy-ethyl)-urea;

[4-(3,3-Dimethyl-2,3-dihydro-indol-1-yl)-pyrimidin-2-yl]-carbamic acidtert-butyl ester;

3-Cyano-N-[4-(7-methoxy-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-pyrimidin-2-yl]-benzamide;

Isoxazol-4-yl-[4-(2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-pyrimidin-2-yl]-amine;

(3,4-Dichloro-phenyl)-[4-(3,4-dihydro-2H-benzo[b][1,4]thiazepin-5-yl)-pyrimidin-2-yl]-amine;

(6-Aziridin-1-yl-pyridin-3-yl)-[4-(5-methanesulfonyl-2,3-dihydro-indol-1-yl)-pyrimidin-2-yl]-amine;

N²-Cyclopropyl-N⁵-[4-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-pyridine-2,5-diamine;and

Benzo[1,3]dioxole-5-carboxylic acid[4-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amide.

The compounds and pharmaceutical compositions of this invention includeall conformational isomers of compounds of formula I (e.g., cis andtrans isomers, whether or not involving double bonds). The compounds ofthe invention include all optical isomers of the compounds of formula I(e.g., enantiomers and diastereomers), as well as racemic,diastereomeric and other mixtures of all such isomers. This inventionfurther relates to tautomers and stereoisomers of the compounds offormula (I), and mixtures of any of the aforementioned forms.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula (I). The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate,lactate, citrate, acid citrate, tartrate, bitartrate, succinate,maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The present invention also relates to the pharmaceutically acceptablebase addition salts of compounds of the formula (I). The chemical basesthat may be used as reagents to prepare pharmaceutically acceptable basesalts of those compounds of formula I that are acidic in nature arethose that form non-toxic base salts with such compounds. Such non-toxicbase salts include, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (e.g.,potassium and sodium) and alkaline earth metal cations (e.g., calciumand magnesium), ammonium or water-soluble amine addition salts such asN-methylglucamine-(meglumine), and the lower alkanolammonium and otherbase salts of pharmaceutically acceptable organic amines.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in Formula (I), but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ³H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of Formula (I) ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the Schemes and/or in theExamples and Preparations below, by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

In the practice of the invention, preferably the mammalian patient is ahuman, but the invention is broadly applicable to the treatment of othermammals, such as farm animals and companion animals.

The present invention relates to a pharmaceutical composition fortreatment or prevention of conditions in a mammalian patient, wheretherapeutic benefit is achieved by downregulating T-cell mediated immuneresponse, comprising an effective amount of a compound according toformula I, and a pharmaceutical carrier.

The present invention relates to a pharmaceutical composition for thetreatment or prevention of transplant rejection in a mammal, comprisingan effective amount of a compound according to formula I, and apharmaceutical carrier.

The present invention relates to a pharmaceutical composition fortreatment or prevention of autoimmune disease in a mammal, comprising aneffective amount of a compound according to formula I, and apharmaceutical carrier.

The present invention also relates to a pharmaceutical composition fortreating inflammatory disease in a mammal, comprising an effectiveamount of a compound according to formula I, and a pharmaceuticalcarrier.

The present invention also relates to a pharmaceutical composition fortreating allergy in a mammal, comprising an effective amount of acompound according to formula 1, and a pharmaceutical carrier.

The present invention also relates to a pharmaceutical composition fortreating T-cell leukemias and T-cell lymphomas in a mammal, comprisingan effective amount of a compound according to formula I, and apharmaceutical carrier.

The present invention also relates to a pharmaceutical composition forthe treatment of diseases in a mammal, wherein treatment can be effectedby inhibiting activation of T-cells, or the results of said activation,comprising an effective amount of a compound according to formula I, anda pharmaceutical carrier.

The present invention relates to a method for treating or preventingtransplant rejection in a mammal.

The present invention further relates to a method for treating orpreventing autoimmune disease in a mammal.

The present invention further relates to a method for treating orpreventing allergic disease in a mammal.

The present invention further relates to a method for treating orpreventing inflammatory disease in a mammal.

The present invention also relates to inhibiting T-cell mediated immuneresponse in a mammalian patient, wherein this is beneficial to themammal nothwithstanding that said immune function was within the normalrange.

In the practice of said methods, there is administered a pharmaceuticalcomposition of the invention comprising a compound according to formulaI, and a pharmaceutical carrier.

An additional embodiment of the invention includes a compound of formula(I), or a pharmaceutically acceptable salt, solvate, or hydrate of anysuch compound, for administration in pharmaceutically acceptable form,in combination with one or more additional agents which have ananti-inflammatory effect, or which themselves can modulate one or morecomponents or processes of the mammalian immune system.

Definitions

In connection with the practice of the invention, the followingdefinitions will generally apply.

The term “treating”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such disorder orcondition. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

The term “transplant” refers to transplanted cells, tissues, and organsor portions of organs. The term “transplant” also refers tomacromolecules that are normally associated with the transplanted cells,tissues, and organs, whether intracellular, membrane associated, orextracellular in nature. In this regard, a category of macromoleculesthat is of particular interest refers to those associated with theextracellular matrix of a transplanted tissue. T-cell mediated immuneresponse against such macromolecules can cause failure of the transplantas a whole. “Transplant” includes both allografts and xenografts.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof. Similarly, the terms “alkenyl”and “alkynl” define hydrocarbon radicals having straight, branched orcyclic moities wherein at least one double bond, or at least one triplebond, respectively, is present. Such definitions also apply when thealkyl, alkenyl or alkynyl group is present within another group, such asalkoxy or alkylamine.

The term “alkoxy”, as used herein, includes O-alkyl groups wherein“alkyl” is as defined above.

The term “halo”, as used herein, unless otherwise indicated, includesfluoro, chloro, bromo or iodo.

An “aryl” group as used herein, unless otherwise indicated, includes anorganic radical derived from a monocyclic or bicylic (C₆-C₁₀) aromatichydrocarbon compound by removal of a hydrogen radical from a ring carbonof the aryl compound. An aryl group is optionally substituted by one ormore substituents wherein, unless otherwise indicated, selection of eachoptional substituent is independent of selection of any other optionalsubstituents, and perferably the number of optional substituents isbetween 0 and 3, more preferably between 0 and 2. It will be appreciatedthat the preferred number of substituents is determined in part byfacility of synthesis. Representative aryl groups are phenyl andnaphthyl.

A “heteroaryl” group as used herein, unless otherwise indicated,includes an organic radical derived from a monocyclic or bicyclic(C₁-C₉) aromatic heterocyclic compound by removal of a hydrogen radicalfrom a ring atom of the heteroaryl compound, said ring atom beinguncharged in said compound. A heteroaryl group is optionally substitutedby one or more substituents wherein, unless otherwise indicated,selection of each optional substituent is independent of selection ofany other optional substituents, and perferably the number of optionalsubstituents is between 0 and 3, more preferably between 0 and 2. Itwill be appreciated that the preferred number of substituents isdetermined in part by facility of synthesis. Representative heteroaryl-groups include furyl-, thienyl-, thiazolyl-, pyrazolyl-, isothiazolyl-,oxazolyl-, isoxazolyl-, pyrrolyl-, triazolyl-, tetrazolyl-, imidazolyl-,1,3,5-oxadiazolyl-, 1,2,4-oxadiazolyl-, 1,2,3-oxadiazolyl-,1,3,5-thiadiazolyl-, 1,2,3-thiadiazolyl-, 1,2,4-thiadiazolyl-, pyridyl-,pyrimidyl-, pyrazinyl-, pyridazinyl-, 1,2,4-triazinyl-,1,2,3-triazinyl-, 1,3,5-triazinyl-, pyrazolo[3,4-b]pyridinyl-,cinnolinyl-, pteridinyl-, purinyl-, 6,7-dihydro-5H-[1]pyrindinyl-,benzo[b]thiophenyl-, 5,6,7,8-tetrahydro-quinolin-3-yl-, benzoxazolyl-,benzothiazolyl-, benzisothiazolyl-, benzisoxazolyl-, benzimidazolyl-,thianaphthenyl-, isothianaphthenyl-, benzofuranyl-, isobenzofuranyl-,isoindolyl-, indolyl-, indolizinyl-, indazolyl-, isoquinolyl-,quinolyl-, phthalazinyl-, quinoxalinyl-, quinazolinyl-, andbenzoxazinyl-; and the like.

A “cycloalkyl” group as used herein, unless otherwise indicated,includes an organic radical derived from a monocyclic(C₃-C₁₀)cycloalkyl- compound, by removal of a hydrogen radical from aring carbon of the cycloalkyl- compound. A cycloalkyl- group isoptionally substituted by one or more substituents wherein, unlessotherwise indicated, selection of each optional substituent isindependent of selection of any other optional substituents, andperferably the number of optional substituents is between 0 and 3, morepreferably between 0 and 2. It will be appreciated that the preferrednumber of substituents is determined in part by facility of synthesis.Representative cycloalkyl- groups include cyclopropyl-, cyclobutyl-,cyclopentyl-, cyclohexyl-, cycloheptyl-, cyclopropenyl-, cyclobutenyl-,cyclopentenyl-, cyclohexenyl-, cycloheptenyl-, 1,3-cyclobutadienyl-,1,3-cyclopentadienyl-, 1,3-cyclohexadienyl-, 1,4-cyclohexadienyl-,1,3-cycloheptadienyl-, 1,4-cycloheptadienyl-, bicyclo[3.2.1]octane-,bicyclo-[2.2.1]heptane-, and the norborn-2-ene unsaturated form thereof.Thus, the term cycloalkyl- also includes cycloalkenyl- groups having oneor two double bonds.

A “heterocycloalkyl” group as used herein, unless otherwise indicated,includes an organic radical derived from a monocyclic(C₃-C₁₀)heterocycloalkyl compound by removal of a hydrogen radical froma ring atom of the heterocycloalkyl compound. A heterocycloalkyl groupis optionally substituted by one or more substituents wherein, unlessotherwise indicated, selection of each optional substituent isindependent of selection of any other optional substituents, andperferably the number of optional substituents is between 0 and 3, morepreferably between 0 and 2. It will be appreciated that the preferrednumber of substituents is determined in part by facility of synthesis.Representative heterocycloalkyl- groups include pyrrolidinyl-,tetrahydrofuranyl-, dihydrofuranyl-, tetrahydropyranyl-, pyranyl-,thiopyranyl-, aziridinyl-, oxiranyl-, methylenedioxyl-, chromenyl-,isoxazolidinyl-, 1,3-oxazolidin-3-yl-, isothiazolidinyl-,1,3-thiazolidin-3-yl-, 1,2-pyrazolidin-2-yl-, 1,3-pyrazolidin-1-yl-,piperidinyl-, thiomorpholinyl-, 1,2-tetrahydrothiazin-2-yl-,1,3-tetrahydrothiazin-3-yl-, tetrahydrothiadiazinyl-, morpholinyl-,1,2-tetrahydrodiazin-2-yl-, 1,3-tetrahydrodiazin-1-yl-,tetrahydroazepinyl-, piperazinyl-, and chromanyl-.

In connection with the terms “aryl” group, “heteroaryl” group,“cycloalkyl” group and “heterocycloalkyl” group, as herein defined, theterm “optionally substituted” means that one or more chemically andpharmaceutically acceptable functional groups may be bonded thereto.Such a group contributes properties useful to production, storage, oruse of the inventive compounds as pharmaceuticals, or at least does notsubstantially negate their pharmacological activity. Such suitablesubstituents may be determined by those skilled in the art. Illustrativeexamples of suitable substituents include, but are not limited to,hydroxy, halo, amino, trifluoromethyl, carboxy, (C₁-C₆)alkoxy-,(C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-,(C₁-C₆)acylamino-, cyano, nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-,C₂-C₆)alkynyl-, (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-, nitro(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acylamino-,amino(C₁-C₆)acyl-, amino(C₁-C₆)acyl(C₁-C₆)alkyl-,(C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-, (C₁-C₆)acyloxy(C₁-C₆)alkyl-,(C₂-C₆)alkoxy(C₁-C₆)alkyl-, piperazinyl(C₁-C₆)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₂-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-(C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-,(C₁-C₆)alkyl(difluoromethylene)-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acyl-,(C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-,(C₆-C₁₀)aryl-, (C₅-C₉)heteroaryl-, (C₆-C₁₀)aryl(C₁-C₆)alkyl-,(C₂-C₉)heteroaryl(C₁-C₆)alkyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₆)alkyl-(C₃-C₁₀)cycloalkyl-,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl-, (C₃-C₁₀)heterocycloalkyl-,(C₃-C₁₀)heterocycloalkyl(C₁-C₆)alkyl-, hydroxy(C₂-C₆)alkyl-,(C₁-C₆)acyloxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy(C₂-C₆)alkyl-,piperazinyl(C₁-C₆)alkyl-, (C₁-C₆)acylamino(C₁-C₆)alkyl-,(C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₂-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-, and((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl.

The present invention, and additional embodiments thereof, are furtherdescribed in the detailed description of the invention which followsdirectly.

DETAILED DESCRIPTION OF THE INVENTION

Practice of the Invention

Characterized in its broadest sense, the present invention is directedto recognizing conditions where therapeutic benefit can be achieved bydownregulating T-cell mediated immune response. Depending on theinvolved clinical condition, the immune response that is downregulatedmay be normal or abnormal, or otherwise beneficial. In a preferredembodiment of the invention, therapeutic modulation of T-cell mediatedprocesses is achieved in a mammalian patient through the administrationof compounds that interefere with, or otherwise modify, T-cellactivation, and/or other T-cell functions that result from suchactivation. Generally speaking, such events binding of an antigen(including a self-antigen) to a T-cell.

T-cell mediated immune responses are involved, for example, indelayed-type hypersensitivity, lysis of tumor cells or cells thatexpress viral antigens, resistance to intracellular pathogens, allergiccontact dermatitis, rejection of allografts and xenografts, graft versushost reactions, certain autoimmune diseases, and various types ofallergy. Preventing activation of T-cells thus represents an importantpoint of intervention for cell mediated immune responses when this istherapeutically appropriate.

For purposes of description, clinical conditions that can be treatedaccording to the practice of the present invention may be divided intothree principal categories:

(1) prevention of transplant rejection, where cells, tissues, or organs(or parts thereof) have been transplanted into a patient, and the normaland otherwise proper immune response against the transpant must beprevented;

(2) treatment of various disease states where “normal” immune systemaction leads, directly or indirectly, to clinical manifestations thatare not desired, for example is circumstances involving damaginginflammation, and allergy; and

(3) various disease states, characterized in whole or part as autoimmunediseases, wherein an immune response is mounted against the body's owntissues.

The present invention is practiced with respect to all of the diseases,clinical conditions, and the like, that are discussed below.

Of course, given the complex nature of many disease states or clinicalconditions, more than one of the above categories may be relevant inparticular circumstances. It must be emphasized that these categoriesare arbitrary and merely descriptive. For example, with respect toinsulin dependent (juvenile/type I) diabetes (see below), treatment atonset is best characterized as prevention of autoimmune disease, whereasimmune suppression in the mature disease may be for the purpose ofprotecting transplanted pancreatic beta cells.

An additional category relates to suppression of an immune responseagainst a therapeutic macromolecule that is administered to (orexpressed in) a patient, wherein said macromolecule is otherwise foreignto the patient. Examples include proteins expressed from gene therapyand covalently modified proteins, such as PEGylated proteins. It shouldbe noted that, on occasion, immune response can also occur even againsta protein that has an amino acid sequence identical to that encoded by apatient's own genome. Under these circumstances, the protein may havebeen expressed in the body at levels, or in places, that are atypical,or in an atypical combination with other macromolecules, or the immuneresponse may occur for unknown reasons.

In elaboration of these demonstrative categories, examples ofcircumstances where it is appropriate to prevent activation of T-cells,and/or to down regulate T-cell mediated immune response, are as follows.

(1) Organ, tissue, and cell transplants between individuals of the samespecies (allograft transplantations) are an important medical procedurefor which there is often no substitute, since the complicated functionsof the kidney, heart, bone marrow, lung, or liver, for example, cannotbe duplicated. Unfortunately, transplants between individuals very oftenend in rejection of the transplant. For example, if an allograft ofdonor skin is positioned on an excised area of a recipient patient, thegraft will at first successfully vascularize and proliferate. However,after a brief period of time (perhaps 7-10 days), the site typicallybecomes subject to severe inflammation, and the transplanted skinwithers and is sloughed. A repeat transplant from the same donor issubject to more rapid rejection. It is well known that such events aremediated by transplantation antigens including the majorhistocompatibility complex of glycoproteins (MHC, also termed HLA inhumans) which are expressed from perhaps 20 genes. The HLA proteinproducts, when expressed on cell surfaces, play a major role inpresenting peptide fragments of antigen to T-cells at theirantigen-specific receptors, the TcR. The HLA glycoproteins varytremendously from individual to individual, and when recognized byreceptive T-cells, are responsible for the typically complete rejectionof the donor tissue. Interfering with activation of the T-cells, willpermit a wider variety of transplant procedures to be successfullyperformed.

Xenograft transplants are also subject to rejection. Important examplesof such transplants include primate-to-human and pig-to-human, andinvolve numerous organs and tissues including, without limitation, heartand heart valve, kidney, skin, pancreas, and the like.

(2) It is well known that antigens can elicit inflammatory responseshaving an intensity that does not necessary correlate with the level ofcirculating antibodies. Delayed-type hypersensitivity (DTH) reactionsare an example of such responses, in which activated T-cellsparticipate.

In a general sense, inflammation is a protective response to localinjury or other abnormal condition, and involves blood vessels, cellsthat circulate in the blood vessels, and nearby connective tissue. Theearly phase of an inflammatory response typically begins with hyperemia,edema, and margination of circulating white blood cells. The white bloodcells (including phagocytic leukocytes, and lymphocytes) then penetratebetween the endothelial cells of the blood vessel wall, and enter thetissue. The leakage of water and protein into the damaged area (edema)also permits entry of antibodies, facilitates washing away of toxicsubstances and debris, and permits direct contact of defending whitecells, including phagocytic cells, with infecting agents. Localinflammatory responses are also associated with systemic changesincluding fever, and an increase in the number of circulatingleukocytes.

A large number of additional cellular components participate in theinflammatory response. In this regard, the complement system should bementioned. Complement consists of about 25-30 proteins, some of whichcirculate in blood plasma, and some of which are membrane bound. Somecomplement proteins bind, in an ordered sequence, to antigen-antibodycomplexes on target cells, facilitating cell lysis. Other complementproteins facilitate clearance of antibody-antigen complexes from thebody, others prevent cell lysis or excessive inflammation, while peptidefragments of other complement proteins stimulate inflammation.

Particular proinflammatory activities of activated complement proteins(and their fragments) include: release of histamine and other vasoactivemediators from mast cells to increase permeability of the capillaries atan affected site; attracting polymorphonuclear leukocytes andmacrophages to sites of inflammation and enhancing the activity thereof;lysis of gram negative bacteria, and damage to the membranes of manyother types of targeted cells, including self cells, bearing foreignantigens; and facilitating adherence of leukocytes and macrophages tothe surface of cells targeted for ingestion (such as bacteria andviruses, or self cells) via antigen-antibody complexes.

General interrelationships between the immune system, the complementsystem, and inflammatory conditions are well recognized in the art. Forexample, CD4+ T-cells are known to release lymphokines, such asλ-interferon, which stimulate macrophages to release substances thatincrease inflammation at an affected site, permitting destruction ofinvading pathogens. It is thus apparent that the inflammatory response,and cell mediated immune processes, reflect a complex set ofinterrelated mechanisms that permit response to injury, and infection.Unfortunately, the component pathways of this complex systemoccasionally work in ways adverse to the body, preventing appropriateresponse to disease states, or actually causing the disease statesthemselves. As a result, the specificity of the compounds of theinvention contribute to their therapeutic value.

Particular inflammatory diseases that may be treated according to thepractice of the invention include psoriasis, and inflammatory diseasesof the gastrointestinal tract such as ulcerative colitis and Crohn'sdisease.

An additional category of inappropriate immune response includes thoseprocesses involving antibody-mediated (intermediate-type)hypersensitivity reactions (typically involving IgE antibodies), andwhich are often termed allergies. Generally speaking, allergy orhypersensitivity may be defined as an altered state, induced by anantigen, in which pathologic reactions can be subsequently elicited byexposure to that antigen, or to structurally similar substances.Representative examples include asthma, hay fever, hives, infantileeczema, atopic dermatitis, and gastrointestinal disturbances. ActivatedT-cells are also involved in these inappropriate immune responses.

(3) A considerable number of disease states involve circumstances wherean individual produces antibodies and reactive T-cells against his orher own proteins or cells. Such circumstances are a significantexception to the general principle of self-tolerance, whereinbyself-molecules do not trigger an immune response. A significant numberof mechanisms are recognized whereinby an autoimmune response to aself-antigen can be triggered. Self-antigens may represent self-proteinsthat are denatured or otherwise modified after being produced onribosomes, thus exposing novel epitopes (immune-recognized domains,typically short peptide or carbohydrate sequences) which are then takenup and processed by antigen-presenting cells and made available toreceptive T-cells. Loss of thyroid function following chronicinflammation of the thyroid (Hashimoto's disease) may involve such anautoimmune pathway. Another thyroid pathology, thyroiditis followed byhyperthyroidism, may be explained by immune recognition of the cellsurface receptor for thyroid stimulating hormone, however with the lesstypical result that antibody binding to the recognized cells results intheir stimulation, not death.

Similarly, an autoimmune response may be mounted against an altereddistribution of self-antigen. For example, self antigen from an organmay be exposed only after serious injury, and immune-mediatedinflammation (see below) may then enhance and perpetuate the primaryresponse. Persistent viral infections may also trigger autoimmune-likedisease. It is not uncommon for host antibodies to bind to viralparticles without neutralizing them, and it is possible that theresulting virus-antibody complexes may, over time, result in theproduction of what appear to be anti-self antibodies. Additionally, itis thought that certain T-cells termed Supressor Cells(T_(s)) may act tosuppress immune response to particular self-antigens. Defectiveproduction of such T_(s) cells could permit activation of autoreactiveT-cells whose action would need to be suppressed by therapeuticintervention.

Finally, many of the most widespread and serious autoimmune diseases mayhave their origin in the phenomenon of antigenic mimicry. The epitopes(immune-recognized domains) of antigens of infecting bacteria andviruses may bear considerable resemblance to similar structural motifs(for example peptide sequences) in mammalian proteins. Thus, an immuneresponse intended to be specific against structural features of aninvading pathogen may unfortunately also target identical or nearlyidentical macromolecular structural elements of self proteins.

Infections with some viruses are statistically associated with the onsetof myasthenia gravis and insulin-dependent (juvenile/type I) diabetes.In type I diabetic disease, the panceatic beta (islet) cells thatproduce insulin are selectively destroyed. The human disease appears todepend on activated CD4+ T-cells and corrleates with the inheritedpresence in patients of specific HLA alleles (for example, DR3 or DR4homozygotes, and DR4/DR3 heterozygotes have a high probability ofcontracting the disease). Although the exact beta cell autoantigen andautoantigen epitope(s) are unknown, homology with a Coxsackie B virusprotein is suspected. It has been proposed that in susceptibleindividuals, having particular HLA alleles, presentation of viralantigen to T-cells unfortunately leads to cross-recognition of beta cellsurface proteins by the immune system, with the result of gradual deathof the entire beta cell population.

Thus, as the type I disease progresses, the patient becomes insulindependent. However, diagnostic procedures for susceptibility to type Idisease are known in the art, and the at-risk patient can be placed on aprogram of life-long immune suppression to prevent full onset of theautoimmune disease (thereby protecting surviving insulin-producingpancreatic cells). In those cases where no insulin producing cellssurvive (full type I disease), the disease may be treated bytransplantation of pancreatic islet cells. In such case, the approach ofthe present invention is best characterized as prevention of transplantrejection.

The mechanisms of causation and progression for rheumatoid arthritisappear to share in-common features with those for type I diabetes. Inrheumatoid arthritis, synovial membranes enclosing joint spaces aresubject to very pronounced infiltration by lymphocytes, macrophages, andother cells. Compared to a control population, rheumatoid arthritispatients tend to express DR4, DR1, and DRw10 HLA haplotypes at highfrequency. It is again likely that presentation of a self peptide byparticular surface HLA molecules to receptive T-cells is essential todevelopment of the disease. Consequently, suppression of resultantT-cell activation, and downstream signalling events, is an importantstrategy for therapeutic intervention. Additional autoimmune diseasesthat can be treated according to the practice of the invention includelupus (including systemic lupus erythematosus and lupus nephritis),pemphigus vulgaris (in which the recognized self-antigen is found inepidermal cells), thrombocytopenic purpura (in which the level offunctional platelets falls to very low levels), and multiple sclerosis(wherein demyelinating activity may result from infection of the nervoussystem by a virus, bringing appropriate antigen in contact withT-cells).

The present invention provides highly specific inhibitors of T-cellIcktyrosine kinase. Administration of such compounds interferes withT-cell activation, and subsequent signalling events, thereby providingan effective means of intervention in the above-identified cell mediatedimmune responses.

The present invention also provides a method of treating or preventingT-cell leukemias, T-cell lymphomas, and other T-cell malignancies,whether the affected cells are primarily circulating or non-circulating.In this embodiment of the invention, it is not necessary that theinvolved T cells be activated.

The present invention also provides a method of treating themultifaceted pathology of Alzheimer's disease, and the complicationsthereof.

Pharmaceutical Formulations

The compounds of the present invention that are basic in nature arecapable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention arereadily prepared, for example, by treating the base compound with asubstantially equivalent amount of the chosen mineral or organic acid inan aqueous solvent medium or in a suitable organic solvent, such asmethanol or ethanol. Upon careful evaporation of the solvent, thedesired solid salt is readily obtained. The desired acid salt can alsobe precipitated from a solution of the free base in an organic solventby adding to the solution an appropriate mineral or organic acid.

Those compounds of the present invention that are acidic in nature, arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., rheumatoidarthritis) is 0.1 to 1000 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

Aerosol formulations for treatment of the conditions referred to above(e.g., asthma) in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains 20 μg to 1000 μg ofthe compound of the invention. The overall daily dose with an aerosolwill be within the range 0.1 mg to 1000 mg. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

As is well recognized, the precise dose, and method and timing ofadministration thereof, are capable of determination by those skilled inthe art, and depend upon numerous factors including the activity of thetherapeutic compound, the properties of the formulation thereof, thenature and location of the target tissue, and the particulars of thedisease state as it exists in a particular patient.

A compound of formula (I) administered in a pharmaceutically acceptableform either alone or in combination with one or more additional agentswhich modulate a mammlian immune system or with one or moreanti-inflammatory agents. Such additional agents may include, but arenot limited to, cyclosporin A (e.g. Sandimmune® or Neoral®), rapamycin,FK-506 (tacrolimus), leflunomide, CD40L Ab, methotrexate, FTY720,deoxyspergualin and analogs thereof, mycophenolate (e.g. Cellcept®),azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®), OKT3 (e.g.Orthocolone®), AtGam, aspirin, acctaminophen, ibuprofen, naproxen,piroxicam, and antiinflmmatory steroids (e.g. prednisolone ordexamethasone). Such agents may be administered as part of the same orofg separate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

As examples, FK506 (Tacrolimus) may be given orally at 0.10-0.15 mg/kgbody weight, every 12 hours, within first 48 hours postoperative, forexample. Dose is monitored by measurement of serum Tacrolimus troughlevels.

Cyclosporin A (Sandimmune® oral or intravenous formulation, or Neoral®,oral solution or capsules) may be given orally at 5 mg/kg body weight,every 12 hours within 48 hours postoperative. Dose is monitored bymeasurement of blood cyclosporin A trough levels.

The compounds of the present invention can be formulated for sustaineddelivery according to methods well known to those of ordinary skill inthe art. Examples of such formulations can be found in U.S. Pat. Nos.3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397. Additionally,the compounds of the present invention can be formulated usingtehcnologies that provide continuous dosing via the digestive tractincluding, for example, osmotic systems, such as described in U.S. Pat.No. 4,612,008.

Synthesis of Compounds of the Invention

The following reaction schemes illustrate preparation of compounds ofthe present invention.

General Reaction Conditions

Generally speaking, the compounds of the invention are made in a twostep process. First, the reactive nitrogen atom of compound 4 (indicatedby an arrow above) preferentially displaces the 4-chloro group of2,4-dichloropyrimidine (compound 3) under basic conditions to formcompound 2. In a second step, generally in the presence of an acidcatalyst, compound 2 is treated with an amine to form compound 1,wherein the amine nitrogen displaces the 2-chloro atom of thepyrimidine.

The reaction of compounds 4 and 3 is best conducted under basicconditions. Examples of suitable conditions include refluxing with atrialkylamine such as triethylamine in an alcohol solvent such asethanol. As aforementioned, the 4-chloro group in 2,4-dichloropyrimidineis selectively displaced in the formation of compounds 2.

Subsequent treatment of compound 2 with an amine yields compound 1 asproduct. Selection of the appropriate amine is determined by therequired structure of the product. The reaction solvent is chosen toboth facilitate the solubility of the amine, and its subsequentreaction. For example, in the case of aniline or substituted anilines,the amine may be dissolved in an acetone/water solution in the presenceof a catalytic amount of HCl, followed by heating for 18 hours at 50°C., for example. Mixtures of THF/water also provide combinations ofsolvent and reaction conditions that are generally useful. Conditionssuited to reaction of any particular amine are readily determined.

Some compounds of the invention are made in a two step process shown inScheme II where, in the first step, the reactive nitrogen of a compound4 displaces the 4-chloro group of 2-amino-4-chloropyrimidine (compound5) under basic conditions to form compound 6. In a second step,optionally in the presence of a tertiary amine base such astriethylamine, compound 6 is treated with a suitable agent, such as anacylating or sulfonylating agent to give compound 1. Examples ofsuitable acylating agents include, but are not limited to, acidchlorides, sulfonyl chlorides such as aryl or heteroarylsulfonylchlorides, carbamoyl chlorides, chloroformates, and isocyanates, or acarboxylic acid in the presence of a suitable coupling agent such as a1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in asuitable solvent such as THF. In this regard, it is understood that theacylating agent is chosen to deliver R¹ according to the general formulaI.

Both compound 3 (2,4-dichloropyrimidine) and compound 5(2-amino-4-chloropyrimidine) are readily prepared and commerciallyavailable.

Compounds 4 are also readily prepared, or are commercially available,and may contain one or more optional substituents R², and one or moreoptional substituents R³ (where it is understood that the R³ group isattached to a ring carbon (including at X, if, X is a methylene group),as indicated below.

Representative ring structures for compound 4 include1,2,3,4-tetrahydroquinoline; 1,2,3,4-tetrahydroquinoxaline;3,4-Dihydro-1H-quinoxaline-2-one (2-oxo-1,2,3,4-tetrahydroquinoxaline);3,4-Dihydro-2H-benzo[1,4]oxazine (3,4-2H-2H-benzo(1,4)oxazin-6-ol);2,3-Dihydro-1H-indole; and 3,4-Dihydro-2H-benzo[1,4]thiazine,respectively, as shown below.

Structures 4a to 4f above, for example, are commercially available whereR² and R³ are hydrogen. Additional species that are readily available incommerce include 7-methyl-1,2,3,4-tetrahydroquinoline;6-methyl-1,2,3,4-tetrahydroquinoline;5-methyl-1,2,3,4-tetrahydroquinoline;6-methoxy-1,2,3,4-tetrahydroquinoline;7-trifluoromethyl-1,2,3,4-tetrahydroquinoline;6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline;2-methyl-1,2,3,4-tetrahydroquinoline; 2,3-dihydro-1H-quinolin-4-one;6-methoxy-2,3-dihydro-1H-quinolin-4-one; 2-methyl-2,3-dihydro-1H-indole;2,3-dimethyl-2,3-dihydro-1H-indole; 5-fluoro-2,3-dihydro-1H-indole;5-bromo-2,3-dihydro-1H-indole; 5-methanesulfinyl-2,3-dihydro-1H-indole;5-methanesulfonyl-2,3-dihydro-1H-indole; and 2,3-dihydrobenzothiazole.

With respect to structures of type 4, additional synthetic approachesinclude the following:

(1) with respect to synthesis of the 2,3-dihydro-1H-indole ring system

methods are disclosed in E. C. Taylor et al., Tetrahedron, 43, p. 5145(1987).

(2) with respect to synthesis of the 3,4-Dihydro-1H-quinoxalin-2-onering system

methods are disclosed in R. W. Holley, et al., J. A. Chem. Soc., 74, p.3069, 1952 and R. E. TenBrink, J. Med. Chem. 37, p. 758, 1994;

(3) with respect to synthesis of the1,2,3,4-tetrahydro-[1,5]naphthyridine ring system

methods are disclosed in C. E. Neipp et al., Tetrahedron Letters, 38, p.7499, 1997;

(4) with respect to synthesis of the6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine ring system

methods are disclosed in E. M. Hawes et al., Tetrahedron, 10, p. 39,1973;

(5) with respect to synthesis of the5,6,7,8-tetrahydropyrido{2,3-d]pyrimidine ring system,

methods are disclosed in S. Kobayashi, Bull. Chem. Soc. Jpn., 46, p.2835, 1973, and involve reaction of δ-valerolactam with formamide;

(6) with respect to synthesis of the5,6,7,8-tetrahydropyrrolo{2,3-d]pyrimidine ring system;

methods are disclosed in S. Kobayashi, Bull. Chem. Soc. Jpn., 46, p.2835, 1973, and involve reaction of γ-butyrolactam with formamide;

(7) a large series of pyridopyridines are commercially available thatcan be reduced to the corresponding cyclic amines using known reductionmethods including those cited in N. Ikekawa, et al., Chem. Pharm Bull.,6, p. 408, 1958; W. L. F. Armarego, J. Chem. Soc. (C), VIOL?, p. 377,1967, and H. Rapoport et al., J. Org. Chem., 28, p. 1753, 1963. Forexample,

(8) a large series of cyclic amides and diamides are commerciallyavailable that can be reduced with lithium aluminum hydride, or othersuitable reducing agents as recognized in the art, to give thecorresponding amines. For example,

As aforementioned, preferred R² groups include halo, trifluoromethyl,(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy-, and benzyloxy, for example, andcompounds 4 in Schemes I and II containing them are commerciallyavailable or are readily synthesized.

Additionally, in the case where compound 4 is a1,2,3,4-tetrahydroquinoxaline (4b), a ring nitrogen atom thereof may besubstituted by (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, or phenylsulfonyl,and the like. In such cases it may be preferred to attach thissubstituent after the completion of all other chemistry, for exampleusing an (C₁-C₆)alkylbromide, (C₁-C₆)alkylsulfonylchloride, orphenylsulfonylchloride.

The present invention is evidenced by the following examples.

EXAMPLES Example 1 Preparation of1-[(2-anilino)-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline

6-Methyl-1,2,3,4 tetrahydroquinoline (33.7 mmol) was added to a mixtureof 2,4-dichloropyrimidine (33.5 mmol) and triethylamine (37 mmol) inEtOH (62 mL). The reaction mixture was refluxed for 3 h, cooled to roomtemperature, and the volatiles removed by rotary evaporation. Theremaining solid was extracted with EtOAc/H₂O. The EtOAc layers werecombined, dried over MgSO₄, filtered and the volatiles were then removedrotary evaporation. The residual solid was recrystallized fromEtOAc/hexane to give compound 6, as depicted below,1-(2-Chloro-pyrimidin-4-yl)-6-methyl-1,2,3,4-tetrahydroquinoline.[¹H-NMR(DMSO-d₆): 8.87 (d, J=6, 1H) 7.28 (d, J=8,1H) 7.04 (s, 1H) 7.00(d, J=8, 1H) 6.93 (d, J=6, 1H) 3.79 (m, 2H) 2.65 (m, 2H) 1.85 (m, 2H);m/z 260 (M+1)] The 4-chloro group in 2,4-dichloropyrimidine wasselectively displaced.

Subsequent treatment of compound 8 with the appropriate amine (in thiscase aniline) yields the product 7, in which the 2-chloro atom on thepyrimidine is replaced by the intended substituent. Aniline (0.173 mmol)was added to 1-(2-chloro-pyrimidin-4-yl)-6-methyl-1,2,3,4tetrahyrdoquinoline (0.154 mmol) in 3 mL of acetone/water/ hydrochloricacid (10:15:0.2) and heated to 50° C. for 18 h. The reaction mixture wascooled to room temperature, and the precipitated solid was then filteredand recrystallized from ethyl acetate to give1-[(2-anilino)-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline[¹H-NMR (DMSO-d₆): 7.95 (d, J=8, 1H) 7.54 (d, J=8, 2H) 7.35 (m, 3H) 7.14(m, 1H) 7.08 (m, 2H) 6.60 (d, J=8, 1H) 3.91 (m, 2H) 2.67 (m, 2H) 2.28(s, 3H) 1.93 (m, 2H). m/z: 317(M+1)]

In Examples 2-8 below, synthetic procedures were very similar except forselection of the appropriate amine to react at the 2-chloro position ofthe pyrimidine ring.

Example 21-[2-[(4-bromophenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline

¹H-NMR(DMSO-d₆): 7.96 (d, J=7, 1H) 7.53 (m, 4H) 7.31 (d, J=8 1H) 7.09(s, 1H) 7.07 (d, J=7 1H) 6.60 (d, J=8, 1H) 3.90 (m, 2H) 2.66 (m, 2H)2.28 (s, 3H) 1.91 (m, 2H). m/z: 395,397(M+1)

Example 31-[2-[(4-methoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline

¹H-NMR(DMSO-d₆): 7.88 (b, 1H) 7.41 (d, J=8, 2H) 7.30 (d, J=8, 1H) 7.09(s, 1H) 7.06 (d, J=8, 1H) 6.95 (d, J=8, 2H) 6.55 (d, J=8, 1H) 3.89 (m,2H) 3.74 (s, 3H) 2.67 (m, 2H), 2.28 (s, 3H) 1.91 (m, 2H). m/z: 347(M+1)

Example 41-[2-[(1H-indazole-5-yl)]-4-pyrimidyl]-6-methyl-1,2,3,4-tetrahydroquinoline

¹H-NMR(DMSO-d₆): 9.11 (s, 1H) 8.17 (s, 1H) 7.95 (d, J=6, 1H) 7.84 ( s,1H) 7.49 (d, J=8, 1H) 7.35 ( d, J=8, 1H) 7.27 ( d, J=8, 1H) 6.99 ( s,1H) 6.96 ( d, J=8, 1H) 6.34 (d, J=7, 1H) 3.83 ( m, 2H) 2.64 (m,2H) 2.22(s, 3H) 1.85 (m,2H). m/z: 357 (M+1)

Example 51-[2-[(4-phenoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline

¹H-NMR(DMSO-d₆): 9.20 (s, 1H) 7.94 (d, J=8, 1H) 7.71 (d, J=9 2H) 7.31(m, 2H) 7.24 (d, J=8, 1H) 7.03 (t, J=8, 1H) 6.98 (s, 1H) 6.95 (d, J=81H) 6.90 (m, 4H) 6.37 (d, J=7, 1H) 3.83 (m, 2H) 2.64 (m, 2H) 2.22 (s,3H) 1.85 (m, 2H). m/z: 409 (M=1)

Example 61-[2-[(3,4-dimethoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline

m/z: 377 (M+1)

Example 71-[2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline

m/z: 407 (M+1)

Example 81-[2-[(4,N-phenylaminophenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline

m/z: 408 (M+1)

Example 9[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-amine

m/z 403 (M+1)

Example 105-[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-1,3-dihydro-benzoimidazol-2-one

m/z 373 (M+1)

Example 11(2,3-Dimethyl-1H-indol-5-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine

m/z 384 (M+1)

Example 12[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl-(2-methyl-2H-pyrazol-3-yl)-amine

m/z 321 (M+1)

Example 13(6-Methoxy-pyridin-3-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine

m/z 348 (M+1)

Example 14(4-Fluoro-3-methyl-phenyl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine

m/z 349 (M+1)

Example 15(5-Cyclopropyl-2H-pyrazol-3-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine

m/z 347 (M+1)

Example 16 4-Benzyl-N %3&-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-1H-pyrazole-3,5-diamineExample 17[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(4-methyl-thiazol-2-yl)-amine

m/z 338 (M+1)

Example 18[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(5-methyl-1H-pyrazol-3-yl)-amine

m/z 321 (M+1)

The capability of the compounds of formula (I) to downregulate immunesystem function is demonstrated by the following further examples.

Example 19 Short Term Whole Cell Assay for Compounds than Inhibit Ick,ZAP-70 and itk Enzymes

The present assay measures interleukin-2 (IL-2) secreted from stimulatedT-cells following binding to the cells (at the TcR) by known agonists,anti-CD3 and anti-CD28 antibodies. PTK-inhibitory compounds preventdownstream signalling and activation of the target cells by inhibitingphosphorylation of T-cell polypeptides that is necessary for thedownstream signalling events (following binding to TcR) that otherwiseresult from antigen binding.

In the assay, Jurkat cells are incubated with candidate drug for onehour, and then stimulated with anti-CD3 and anti-CD28 antibodiesprovided on recoverable magnetic beads. After 18 hours of stimulation,cell supernatants are assayed for interleukin 2 by immunoassay. Thefollowing reagents are used in the assay:

(a) Dynabeads® M-450 coated with sheep-antimouse IgG (Dynal Co., productNo. 110.02);

(b) anti-CD3 monoclonal antibody such as “OKT3”, that is capable ofsignaling through the T-cell receptor complex when crosslinked;

(c) anti-CD28 monoclonal antibody, that is capable of signaling throughthe T-cell receptor complex when crosslinked;

(d) RPMI medium (Gibco);

(e) supplemented RPMI, to which 10% fetal calf serum, non essentialamino acids (Gibco # 00467, final conc. is 1/100 that of stock),sufficient penicillin/streptomycin and, optionally, % (w/w) ofL-glutamine have been added;

(f) human IL-2 assay kit, (R&D Systems, catalog No. D2050);

(g) dimethylsulfoxide (DMSO), Sigma Chemical Co., catalog No. D2650;

(h) 96 well flat bottom plates (Costar, catalog No. 3596); and

(i) 96-well polypropylene plates (U-bottom, Costar Catalog No. 3365).

The Dynabeads® are prepared for assay by adding 6 micrograms of theanti-CD28 antibody and 120 micrograms of the anti-CD3 antibody to 4×10⁸beads, in a I ml volumne of Supplemented RPMI solution, followed byincubation for 1-3 hours at room temperature with gentle rocking. Thefully complexed beads are then washed 3 times with 1 ml of RPMI medium,and then diluted to a bead density of 2.5×10⁷/ml in supplemented RPMI.The beads may be stored at 4° C. It will be appreciated that the humanCD3 and CD28 glycoprotein surface antigens have may epitopes againstwhich monoclonal antibodies can be generated, and which possesssufficient affinity to permit proper running of the assay. Generally, itis preferred that the antibodies have a K_(A) of about 10⁻⁸ or lower.Additional anti-human CD3 and anti-CD28 antibodies are known in the art,and/or are available for purchase.

Prior to assay, drug dilution plates must also be prepared. Testcompounds are serially diluted (in triplicate) from 960 micromolar to960 nanomolar on 96-well polypropylene plates using ½ log dilutions. Thediluting solutions contain DMSO at concentrations appropriate to ensurethat test compounds are maintained at 9.6% DMSO (v/v) during thedilutions. The assay itself is inhibited by DMSO and it is essentialthat concentration of DMSO be kept constant.

The test protocol is then as follows. In a typical assay, 5 microlitersof test compound (the concentration range in the final dilution platesis between 960 micromolar and 960 nanomolar) is transfered from thefinal dilution plate to a Jurkat cell test plate (96-well flat bottomplate) which is brought up to 150 microliters final volume withSupplemented RPMI. At the resultant dilution of 1 to 30, the final DMSOconcentration is 0.32% (v/v). 1.25×10⁵ Jurkat cells are then added toeach well (via 125 microliters of Supplemented RPMI medium containingthe cells at a density therein of 1×10⁶/ml). The cells are incubatedwith the test inhibitor compounds for 1 hour at 37° C.

Following this incubation, a 20 microliter quantity of the fullycomplexed bead suspension (at a bead density of 2.5×10⁷/ml insupplemented RPMI) is added to each test well (as a result, 5×10⁵beads/well are used), and the incubation is continued for 18 hours at37° C. The supernatants from each well are transferred to 96-wellV-bottom plates in order to pellet the cells and beads. The supernatantsare then assayed for interleukin-2 with the human IL-2 kit (R&D, #D2050)according to instructions contained therein.

The assay does not specifically discriminate between inhibition ofT-cell activation caused by inhibition of Ick, ZAP-70 and itk PTKenzymes, or any combination thereof, but serves as a useful screen ofpromising compounds. Data are analyzed by polynomial regression andanalzyed using a MACRO program. An IC₅₀ value of less than about 5 μM ispreferred.

Example 20 Screen for Immunosuppressive Compounds that Inhibit theKinase Activity of Ick Enzyme

In the following assay, the potency of a test compound is determined asan IC₅₀ value, that is, the concentration of compound needed, underassay conditions, to inhibit 50% of Ick phosphorylation activity. In thepresent assay, the Ick substrate is “PGT”, poly(glu-tyr) as sodium salt.The following reagents are used in the assay:

(a) DMSO (Sigma, catalog No. D2650);

(b) Dulbecco's medium diluted 1:1 with PBS (Sigma, catalogNo.14190-136);

(c) Tween-20 detergent (Sigma, catalog No. P1379);

(d) bovine serum albumin (Sigma, catalog No. A-7030;

(e) ATP (Sigma, catalog No. A5394);

(f) PGT (Sigma, catalog No. P-0275);

(g) Nunc Maxisorp plates (Van Waters & Rogers, catalog No. 62409-004);

(h) Ick-GST enzyme (a fusion protein of Ick/glutathione —S-transferase,expressed from a Baculovirus vector system, and purified on aglutathione affinity column);

(i) plate coating buffer (100 μg/ml PGT in PBS);

(j) blocking buffer (3% bovine serum albumin in PBS);

(k) phosphorylation buffer (50 mM Hepes, pH 7.4, 125 mM NaCl, 24 mMMgCl₂);

(l) assay buffer (0.3 μM ATP in buffer (k));

(m) wash buffer (0.05% Tween-20 in PBS);

(n) for the detection antibody, the anti-phosphotyrosine antibody,PY-20, provided as a horseradish peroxidase (“HRP”) conjugate (ICNcatalog No. 69-151-1);

(o) TMB Microwell Peroxidase substrate (Kirkegaard and Perry, catalogNo. 50-76-05);

(p) stop solution (0.09M H₂SO₄); and

(q) 96-well polypropylene plates (Costar, U-bottom, catalog No. 3365)

Serial Dilution of Test Compounds on Plates

The test compounds are solubilized in DMSO (100%) and brought to 10 mMas stock solutions. In this representative design, each 96-wellpolpypropylene drug dilution plate contains 3 compounds which areserially diluted 8 times, with a dilution factor of four for eachdilution. The dilutions are performed in 50% DMSO, and set up such thateach serial dilution is done in triplicate.

Prior to dilution 1, the test compound is present at 250 μM (prepared byadding 5 μl of 10 mM compound to 195 μl of 50% DMSO). From this point,consecutive four-fold dilutions are made. For example, dilution 2 ismade by mixing 25 μl from dilution 1 with 75 μl of 50% DMSO, anddilution 3 is made by mixing 25 μl from dilution 2 with 75 μl DMSO, andthe like. Thus, consecutive serial four-fold dilutions will be made at250 μM, 62.5 μM, 15.6 μM, 3.9 μM, 0.98 μM, 0.24 μM, 0.06 μM, and 0.015μM. Accordingly, for test compound 1, the consecutive serial dilutionsproceed from wells A(1-3), to A(4-6), to A(7-9), to A(10-12), to B(1-3),to B(4-6), to B(7-9), to B(10-12). For test compound 2, consecutiveserial dilutions proceed from wells C(1-3), to C(4-6), to C(7-9), toC(10-12), to D(4-6), to D(10-12), to E(1-3), to E(4-6). For testcompound 3, consecutive serial dilutions proceed from wells E(7-9), toE(10-12), to F(1-3), to F(4-6), to F(7-9), to F(10-12), to G(1-3), toG(4-6). Additionally, wells D(1-3) and D(7-9) contain 50% DMSO only (nocompound) and are used as positive and negative controls. All otherwells on the plate, G(7-12) and H(1-12) are left unused. Then, anadditional 25-fold dilution is accomplished when resultant test compoundsamples (5 μl) are transfered from the drug dilution plate to the assayplate wells (see below), each containing 120 μl of assay components.Thus, the concentrations of test compounds in the present assay are 10μM, 2.5 μM, 0.625 μM, 0.156 μM, 0.039 μM, 0.0098 μM, 0.0024 μM, and0.0006 μM. Following the above preparations, the assay itself isperformed as follows.

The Maxisorp assay plates are coated with 100 μl of plate coatingbuffer, covered to prevent evaporation, and incubated overnight at 37°C. It should be noted that the concentration of PGT used is saturating.Following the overnight incubation, the assay plates are rinsed 3 timeswith wash buffer (350 μl/rinse).

From the test compound plate, 5 μl samples of test compound solution areadded to the appropriate wells. Then 100 μl of assay buffer is added toeach well (assay buffer is prepared by adding ATP to the phosphorylationbuffer just prior to assay). Finally, an appropriate amount of LCK,determined by titration, is added to each well in a volume of 20 μl(generally, the LCK level should be near the top of the linear responserange, i.e., about 80% thereof). The loaded assay plates are then shakengently (covering is not necessary) at room temperature for 30 minutes,after which the plates are again washed three times with wash buffer.

To each plate well, 150 μl of blocking buffer is then added, andblocking is performed for 30 minutes at 37° C., during which time theplates are shaken and covered to prevent evaporation. The plates areagain washed 3 times with wash buffer.

The detection antibody stock solution is then diluted 1:2000 in blockingbuffer, and a 50 μl quantity thereof is added to each well, after whichthe plates are again shaken (at room temperature for 25 min), but withno covering needed. The procedure of washing the wells with wash buffer,three times, is repeated.

50 μl of TMB Microwell Peroxidase Substrate is then added to each well,and blue color is allowed to develop (about 1-5 minutes) until the ODvalue for the positive control (450 nm) is about 1.0. At this point, 50μl of stop solution is added to each well and the plate is read on aplate reader (Softmax Pro) at 450 nm.

IC₅₀ values are determined by polynomial regression and analzyed using aMACRO program. An IC₅₀ value of less than about 3 μM is preferred.

1. A compound according to the formula

or pharmaceutically acceptable salts, solvates, or hydrates thereof;wherein each occurrence of A is independently selected from CH or N; Xis selected from the group consisting of —CH₂—, —O—, —NH—,(C₁-C₆)alkylamino-, (C₁-C₆)alkylaminocarbonylamino-,(C₁-C₆)alkylcarbonylamino-, (C₁-C₆)alkylsulfonylamino-,phenylsulfonylamino-, carbonyl, —NH—C(O)—, —N(C₁-C₆)alkyl-C(O)—, —S_(y)— where y is 0, 1 or 2, and; n in —(CH₂)_(n)— is 1, 2 or 3; R¹ isphenyl, optionally substituted with one to five substituents, that areeach independently selected from hydroxy-, halo-, amino-, (C₁-C₆)alkyl-,(C₁-C₆)alkoxy-, trihalo(C₁-C₆)alkyl-, (C₁-C₆)alkynl-, (C₁-C₆)alkylamino-,((C₁-C₆)₂)dialkylamino-, carboxy, (C₁-C₆)alkoxycarbonyl-,(C₁-C₆)acyloxy-, and (C₁-C₆)acylamino- wherein R⁴ is selected from thegroups consisting of (a) (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, or(C₂-C₆)alkynyl-, wherein the alkyl-, alkenyl- and alkynyl- groups areoptionally substituted by hydroxy, halo, amino, trifluoromethyl,hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-,(C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano,nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-, trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, or nitro(C₁-C₆)alkyl-; (b)(C₃-C₁₀)cycloalkyl-, wherein the cycloalkyl- group is optionallysubstituted by hydroxy, halo, amino, trifluoromethyl,hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-,(C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano,nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-, trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, or nitro(C₁-C₆)alkyl-; or(c) (C₃-C₁₀)heterocycloalkyl-, wherein the heterocycloalkyl- group isoptionally substituted by hydroxy, halo, amino, trifluoromethyl,hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-,(C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano,nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-, trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C_(1-C) ₃)alkyl-, or nitro(C₁-C₆)alkyl-;R²represents one to four optional substituents, each being independentlyselected from the members of groups (a) to (f) (a) deuterium, halo,hydroxy, carboxy, amino, trifluoromethyl, (C₁-C₆) alkyl-,(C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, (C₁-C₆)alkylamino-,((C₁-C₆)(alkyl)₂amino-, cyanoalkyl-, (C₃-C₁₀)cycloalkyl,(C₃-C₁₀)heterocycloalkyl-, (C₃-C₁₀ )cycloalkoxy-, (C₁-C₆)alkylthio-,(C₁-C₆)alkylsulfinyl-, (C₁-C₆)alkysulfonyl-, amino-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl-, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkoxy-,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy-, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy-,(C₁-C₆)alkylamino-CO—NH—, (C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl-,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl-,((C₁-C₆)alkyl)₂amino-CO—NH-carboxy, carboxy(C₁-C₆)alkyl-,carboxy(C₁-C₆)alkoxy-, benzyloxycarbony(C₁-C₆)alkoxy-,(C₁-C₆)alkylamino-CO—, (C₁-C₆)acylamino-, (C₁-C₆)alkoxy-, (₁-C6)acyl-,(C₁-C₆)acyloxy-, (C₁-C₆)acyl(C₁-C₆)alkylamino-, (C₁-C₆)alkoxyacyl-,(C₁-C₆)alkylaminoacyl-, ((C₁-C₆)alkyl)₂aminoacyl-, amino(C₁-C₆)acyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkoxycarbonylamino-,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl-,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, trihalomethyl-,trihalomethyl(C₁-C₆)alkyl-, (C₁-C₆)alkyldihalomethylene-,(C₁-C₃)alkyl(dihalomethylene)(C₁-C₃)alkyl-, (C₃-C₆)cycloalkyl-,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl-, hydroxy(C₁-C₆)alkyl-,(C₁-C₆)acyloxy(C₁-C₆)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₁-C₆)alkylthio(C₁-C₆)alkyl-,(C₁-C₆)alkoxycarbonyl-, (C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₁-C₆)alkylsulfonyl-,(C₁-C₆)alkylsulfonylamino-, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-,((C₁-C₆)alkyl₂amino(C₁-C₆)alkyl-, (C₁-C₆)CO(C₁-C₆)alkyl-; (b)(C₆-C₁₀)aryl-, (C₁-C₉)heteroaryl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryl(C₁-C₉)heteroaryl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryl-, (C₁-C₉)heteroaryl(C₆-C₁₀)aryl-,(C₆-C₁₀)arylsulfinyl-, (C₆-C₁₀)aryl(C₆-C₁₀)arylsulfinyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylsulfinyl-, (C₆-C₁₀)arylsulfonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)arylsulfonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylsulfonyl-, (C₁-C₉)heteroarylsulfinyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylsulfinyl-, (C₆-C₁₀)aryl(C₁-C₉)heteroarylsulfinyl-, (C₁-C₉)heteroarylsulfonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylsulfonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylsulfonyl-, (R⁴)sulfinyl-, (R⁴)sulfonyl-,(C₆-C₁₀)aryl(R⁴)sulfinyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(C₆-C₁₀ )aryl(R⁴)sulfinyl-, (C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₆-C₁₀)axyl(C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(R⁴)sulfinyl,(C₆-C₁₀)aryl(C₁-C₉)heteroaryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryl(R⁴)sulfinyl-,(C₁-C₉)heteroaryl(R⁴)sulfonyl-,(C₆-C₁₀)aryl(C₅-C₉)heteroaryl(R⁴)sulfonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryl(R⁴)sulfonyl-,(C₆-C₁₀)arylaminocarbonyl-, (C₆-C₁ O)aryl(C₆-C₁₀)arylaminocarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylaminocarbonyl-,(C₁-C₉)heteroarylaminocarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylaminocarbonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylaminocarbonyl-, (C₆-C₁₀)arylcarbonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)arylcarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)arylcarbonyl-, (C₁-C9)heteroarylcarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroarylcarbonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroarylcarbonyl-, (C₆-C₁₀)aryloxycarbonyl-,(C₆-C₁₀)aryl(C₆-C₁₀)aryloxycarbonyl-,(C₁-C₉)heteroaryl(C₆-C₁₀)aryloxycarbonyl-,(C₁-C₉)heteroaryloxycarbonyl-,(C₆-C₁₀)aryl(C₁-C₉)heteroaryloxycarbonyl-,(C₁-C₉)heteroaryl(C₁-C₉)heteroaryloxycarbonyl-, (R⁴)carbonyl-,(R⁴)oxycarbonyl-, (R⁴)aminocarbonyl-, (C₆-C₁₀)aryl(R⁴)carbonyl-, (C₆-C₁₀)aryl(R⁴)oxycarbonyl-, (C₆-C₁₀)aryl(R⁴)aminocarbonyl-,(C₁-C₉)heteoaryl(R⁴)carbonyl-, (C₅-C₉)heteroaryl(R⁴)oxycarbonyl-,(C₁-C₉)heteroaryl(R⁴)aminocarbonyl-, wherein R⁴ is defined as above, andwherein any of said of (C₆-C₁₀)aryl- or (C₁-C₉)heteroaryl- R² groups maybe optionally substituted by one to five groups independently selectedfrom: (i) hydroxy, halo, amino, trifluoromethyl, carboxy,(C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-,((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano, nitro, (C₁-C₆)alkyl-,(C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-, or nitro(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acylamino-,amino(C₁-C₆)acyl-, amino(C₁-C₆)acyl(C₁-C₆)alkyl-,(C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-,(C₃-C₁₀)cycloalkyl(C₁-C₆)alkyl-, (C₁-C₆)acyloxy(C₁-C₆)alkyl-,(C₂-C₆)alkoxy(C₁-C₆)alkyl-, piperazinyl(C₁-C₆)alkyl-,(C₁-C₆)acylamino(C₁-C₆)alkyl-, (C₆-C₁₀ )aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀)arylthio(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfonyl(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-,(C₁-C₆)alkyl(difluoromethylene)-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, (C₁-C₆)alkoxy(C₁-C₆)acyl-,(C₁-C₆)alkylamino(C₁-C₆)acyl-, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl-(C₆-C₁₀)aryl-, (C₁-C₉)heteroaryl-, (C₆-C₁₀)aryl(C₁-C₆)alkyl-,(C₁-C₉)heteroaryl(C₁-C₆)alkyl-, (C₆-C₁₀)aryl(C₆-C₁₀)aryl-, (C₆-C₁₀)aryl(C₆-C₁₀ )aryl(C₁-C₆)alkyl-, (C₃-C₁₀)cycloalkyl-,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl-, (C₃-C₁₀)heterocycloalkyl-,(C₃-C₁₀)heterocycloalkyl(C₁-C₆)alkyl-, hydroxy(C₂-C₆)alkyl-,(C₁-C₆)acyloxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy(C₂-C₆)alkyl-,piperazinyl(C₁-C₆)alkyl-, (C₁-C₆)acylamino(C₁-C₆)alkyl-,(C₆-C₁₀)aryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₉)heteroaryl(C₁-C₆)alkoxy(C₁-C₆)alkyl-,(C₁-C₆)alkylthio(C₁-C₆)alkyl-, (C₆-C₁₀ )arylthio(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfinyl(C₁-C₆)alkyl-, (C₆-C₁₀)arylsulfinyl(C₁-C₆)alkyl-,(C₁-C₆)alkylsulfonyl(C₁-C₆)alkyl-, (C₆-C₁₀)axylsulfonyl(C₁-C₆)alkyl-,amino(C₁-C₆)alkyl-, (C₁-C₆)alkylamino(C₁-C₆)alkyl-,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl-; (ii) R⁵OCO(C₁-C₆)alkyl- wherein R⁵ isselected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₆-C₁₀)aryl(C₁-C₆)alkyl-, (C₁-C₉)heteroaryl(C₁-C₆)alkyl-; (iii)R⁶(C₂-C₆)alkyl- wherein R⁶ is selected from the group consisting ofpiperazino, (C₁-C₆)acylpiperazino-, (C₆-C₁₀)arylpiperazino-,(C₅-C₉)heteroarylpiperazino-, (C₁-C₆)alkylpiperazino-,(C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpiperazino-, morpholino-,(C₁-C₆)acylmorpholino-, (C₆-C₁₀)arylmorpholino-,(C₁-C₉)heteroarylmorpholino-, (C₁-C₆)alkylmorpholino-,(C₆-C₁₀)aryl(C₁-C₆)alkylmorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylmorpholino-, thiomorpholino-,(C₁-C₆)acylthiomorpholino-, (C₆-C₁₀)arylthiomorpholino-,(C₁-C₉)heteroarylthiomorpholino-, (C₁-C₆)alkylthiomorpholino-,(C₆-C₁₀)aryl(C₁-C₆)alkylthiomorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiomorpholino-, piperidino-,(C₁-C₆)acylpiperidino-, (C₆-C₁₀)arylpiperidino-,(C₁-C₉)heteroarylpiperidino-, (C₁-C₆)alkyl piperidino-,(C₆-C₁₀)aryl(C₁-C₆)piperidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpiperidino-, pyrrolidino-,(C₁-C₆)acylpyrrolidino-, (C₆-C₁₀)arylpyrrolidino-,(C₁-C₉)heteroarylpyrrolidino-, (C₁-C₆)alkylpyrrolidino-,(C₆-C₁₀)aryl(C₁-C₆)alkylpyrrolidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpyrrolidino-, (C₁-C₆)alkoxy(C₁-C₆)acyl-,(C₁-C₆)alkylamino(C₆-C₁₀ )aryl-, and ((C₁-C₆)alkyl₂amino(C₁-C₆)acyl-;(c) R⁷, or R⁷Y-, where R⁷ is selected from the group consisting ofpiperazino-, (C₆-C₁₀)arylpiperazino-, (C₁-C₉)heteroarylpiperazino-,(C₁-C₆)alkylpiperazino-, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino-,(C₁-C₉)heteroaryl(C₁C₆)alkylpiperazino-, morpholino-,(C₆-C₁₀)arylmorpholino-, (C₁-C₉)heteroarylmorpholino-,(C₁-C₆)alkylmorpholino-, (C₆- R²represents one to four optionalsubstituents, each being independently selected from the members ofgroups (a) to (f) (a) deuterium, halo, hydroxy, carboxy, amino,trifluoromethyl, (C₁-C₆) alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₁-C₆)alkylamino-, ((C₁-C₆)(alkyl)₂amino-, cyanoalkyl-,(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)heterocycloalkyl-, (C₃-C₁₀ )cycloalkoxy-,(C₁-C₆)alkylthio-, (C₁-C₆)alkylsulfinyl-, (C₁-C₆)alkysulfonyl-,amino-CO—NH—, (C₁-C₆)alkoxy-CO—NH—, (C₁- (b) (C₃-C₁₀)cycloalkyl-,wherein the cycloalkyl- group is optionally substituted by hydroxy,halo, amino, trifluoromethyl, hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-,(C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-,(C₁-C₆)acylamino-, cyano, nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-,(C₂-C₆)alkynyl-, (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, or nitro(C₁-C₆)alkyl-; or(c) (C₃-C₁₀)heterocycloalkyl-, wherein the heterocycloalkyl- group isoptionally substituted by hydroxy, halo, amino, trifluoromethyl,hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-,(C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano,nitro, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-, trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, or nitro(C₁-C₆)alkyl-;C₁₀)aryl(C₁-C₆)alkylmorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylmorpholino-, thiomorpholino-,(C₆-C₁₀)arylthiomorpholino-, (C₁-C₉)heteroarylthiomorpholino-,(C₁-C₆)alkylthiomorpholino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiomorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiomorpholino-, piperidino-,(C₆-C₁₀)arylthiopiperidino-, (C₁-C₉)heteroarylthiopiperidino-,(C₁-C₆)alkylthiopiperidino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiopiperdino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiopipendino-, pyrolidino-,(C₆-C₁₀)arylthiopyrolidino-, (C₁-C₉)heteroalylthiopyrolidino-,(C₁-C₆)alkylthiopyrolidino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiopyrolidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiopyrolidino-, and Y, if present, isselected from the group consisting of (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-,(C₂-C₆)alkynyl-, amino, oxygen, thio, sulfinyl, sulfonyl,halo(C₂-C₆)alkyl-, and hydroxy(C₂-C₆)alkyl-; (d) ZR⁸—, where R⁸ isselected from the group consisting of piperazino-,(C₆-C₁₀)arylpiperazino-, (C₁-C₉)heteroarylpiperazino-,(C₁-C₆)alkylpiperazino-, (C₆-C₁₀)aryl(C₁-C₆)alkylpiperazino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylpiperazino-, morpholino-,(C₆-C₁₀)arylmorpholino-, (C₁-C₉)heteroarylmorpholino-,(C₁-C₆)alkylmorpholino-, (C₆-C₁₀)aryl(C₁-C₆)alkylmorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylmorpholino-, thiomorpholino-,(C₆-C₁₀)arylthiomorpholino-, (C₁-C₉)heteroarylthiomorpholino-,(C₁-C₆)alkylthiomorpholino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiomorpholino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiomorpholino-, piperidino-,(C₆-C₁₀)arylthiopiperidino-, (C₁-C₉)heteroarylthiopiperidino-,(C₁-C₆)alkylthiopiperidino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiopiperidino-,(C₁-C₉)heteroaryl(C₁-C₆)alkylthiopiperidino-, pyrolidino(C₆-C₁₀)arylthiopyrolidino-, (C₁-C₉)heteroarylthiopyrolidino-,(C₁-C₆)alkylthiopyrolidino-, (C₆-C₁₀)aryl(C₁-C₆)alkylthiopyrolidino-,(C₁-C₉)heteroaryl(C_(1-C) ₆)alkylthiopyrolidino-, and Z is selected fromthe group consisting of (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,amino, oxygen, thio, sulfinyl, sulfonyl, halo(C₁-C₆)alkyl-, andhydroxy(C₂-C₆)alkyl-; (e) two or more of R², when vicinal, together toform one or more further rings of 4, 5, 6 or 7 member atoms selectedfrom the group consisting of phenyl-, naphthyl-, furyl-, thienyl-,thiazolyl-, pyrazolyl-, isothiazolyl-, oxazolyl-, isoxazolyl-,pyrrolyl-, triazolyl-, tetrazolyl-, imidazolyl-, 1,3,5-oxadiazolyl-,1,2,4-oxadiazolyl-, 1,2,3-oxadiazolyl-,1,3,5-thiadiazolyl,-1,2,3-thiadiazolyl-, 1,2,4-thiadiazolyl-, pyridyl-,pyrimidyl-, pyrazinyl-, pyridazinyl-, 1,2,4-triazinyl-,1,2,3-triazinyl-, 1,3,5-triazinyl-, pyrazolo[3,4-b]pyridinyl- ,cinnolinyl-, pteridinyl-, purinyl-, 6,7-dihydro-5H-[1]pyrindinyl-,benzo[b]thiophenyl-, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl-,benzothiazolyl-, benzisothiazolyl-, benzisoxazolyl-, benzimidazolyl-,thianaphthenyl-, isothianaphthenyl-, benzofuranyl-, isobenzofuranyl-,isoindolyl-, indolyl-, indolizinyl-, indazolyl-, isoquinolyl-,quinolyl-, phthalazinyl-, quinoxalinyl-, quinazolinyl-, benzoxazinyl-,and wherein said ring(s) are optionally substituted by one or more(C₁-C₆)alkyl-, (C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-, amino-, halo-,hydroxy-, carboxy-, thiol-, nitro-, cyano-, sulfonic-,halo(C₁-C₆)alkyl-, and hydroxy(C₂-C₆)alkyl-; and (f) two or more of R²when vicinal, together to form one or more further rings of 3, 4, 5, 6or 7 member atoms selected from the groups consisting of: (i)(C₃-C₁₀)cycloalkyl-, containing zero to two levels of unsaturation,selected from the group consisting of cyclopropyl-, cyclobutyl-,cyclopentyl-, cyclohexyl-, cycloheptyl-, cyclopropenyl-, cyclobutenyl-,cyclopentenyl-, cyclohexenyl-, cycloheptenyl-, 1,3-cyclobutadienyl-,1,3-cyclopentadienyl-, 1,3-cyclohexadienyl-, 1,4-cyclohexadienyl-,1,3-cycloheptadienyl-, 1,4-cycloheptadienyl-, bicyclo[3.2.1]octane-,bicyclo [2.2.1] heptane, the norborn-2-ene unsaturated form thereof,wherein said ring is optionally substituted by hydroxy-, halo-, amino-,trifluoromethyl-, hydroxy(C₂-C₆)alkyl-, (C₁-C₆)alkoxy-,(C₁-C₆)acyloxy-,(C₁-C₆)alkylamino-, ((C₁-C₆)alkyl)₂amino-, (C₁-C₆)acylamino-, cyano-,nitro-, carboxy-, thiol-, sulfonyl-, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-,(C₂-C₆)alkynyl-, (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, halo(C₁-C₆)alkyl- ornitro(C₁-C₆)alkyl-; and (ii) (C₃-C₁₀)heterocycloalkyl- selected from thegroup consisting of pyrrolidinyl-, tetrahydrofuranyl-, dihydrofuranyl-,tetrahydropyranyl-, pyranyl-, thiopyrany-l, aziridinyl-, oxiranyl-,methylenedioxyl-, isoxazolidinyl,- 1,3-oxazolidin-3-yl-,isothiazolidinyl-, 1,3-thiazolidin-3-yl-, 1,2-pyrazolidin-2-yl-,1,3-pyrazolidin-1-yl-, piperidinyl-, thiomorpholinyl-,1,2-tetrahydrothiazin-2-yl-, 1,3-tetrahydrothiazin-3-yl-,tetrahydrothiadiazinyl-, morpholinyl-, 1,2-tetrahydrodiazin-2-yl-,1,3-tetrahydrodiazin-1-yl-, tetrahydroazepinyl-, piperazinyl-,chromenyl-, chromanyl-, where said ring is optionally substituted byhydroxy-, halo-, amino-, trifluoromethyl-, hydroxy(C₂-C₆)alkyl-,(C₁-C₆)alkoxy-, (C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-, cyano-, nitro-,carboxy-, thiol-, sulfonyl-, (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-,(C₂-C₆)alkynyl-, (C₁-C₆)acylamino-, cyano(C₁-C₆)alkyl-,trifluoromethyl(C₁-C₆)alkyl-,(C₁-C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl-, halo(C₁-C₆)alkyl ornitro(C₁-C₆)alkyl-; wherein any (C₁-C₆)alkyl-, (C₂-C₆)alkenyl-,(C₂-C₆)alkynyl-, (C₃-C₁₀ )cycloalkyl- or (C₃-C₁₀ )heterocycloalkyl-groups that are, or comprise a portion of, said one to four optional R²substituents are themselves optionally substituted by deuterium-,hydroxy-, amino-, trifluoromethyl-, cyano-, nitro-, carboxy-,(C₁-C₄)alkoxy-, (C₁-C₆)acyloxy-, (C₁-C₆)alkylamino-,((C₁-C₆)alkyl)₂amino-, (C₁-C₆)alkyl-(C₂-C₆)alkenyl-, (C₂-C₆)alkynyl-,(C₁-C₆)acylamino-, (C₃-C₁₀ )cycloalkyl-, (C₃-C₁₀)heterocycloalkyl-,cyano(C₁-C₆)alkyl-, trifluoromethyl(C₁-C₆)alkyl-, nitro(C₁-C₆)alkyl-,and (C₁-C₆)acylamino; and R³ represents one or more optionalsubstituents on a ring carbon atom, including at X where X is —CH₂—,selected from the groups consisting of (C₁-C₆)alkyl- ,trihalo(C₁-C₆)alkyl-, deuterium, and fluorine.
 2. A compound accordingto claim 1, wherein the structural component thereof that is representedby

represents: 1,2,3,4-tetrahydroquinoline; 1,2,3,4-tetrahydroquinoxaline;3,4-Dihydro-1H-quinoxaline-2-one; 3,4-Dihydro-2H-benzo[1,4]oxazine;2,3-Dihydro-1H-indole; or 3,4-Dihydro-2H-benzo[1,4]thiazine.
 3. Acompound according to claim 2, wherein said structural componentrepresents: 6-methoxy-1,2,3,4-tetrahydroquinoline;4-methyl-1,2,3,4-tetrahydroquinoline;7-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline;8-methyl-1,2,3,4-tetrahydroquinoline;6-hydroxy-1,2,3,4-tetrahydroquinoline;8-chloro-1,2,3,4-tetrahydroquinoline;7-chloro-1,2,3,4-tetrahydroquinoline;6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroquinoline;6,7-dimethyl-1,2,3,4-tetrahydroquinoxaline;1,2,3,4-tetrahydroquinoxaline;1-phenylsulfonyl-1,2,3,4-tetrahydroquinoxaline;6-Methyl-1,2,3,4-Tetrahydroquinoline; 3,4-Dihydro-2H-benzo[1,4]oxazine;5-Fluoro-2,3-dihydro-1H-indole; or 3,3-Dimethyl-2,3-dihydro-1H-indole.4. A compound according to claim 1 wherein R¹ is 3,4,5-trimethoxyphenyl.5. A compound according to claim 1 wherein one or more of substituentsR² is selected from the groups consisting of (a) (C₁-C₆)alkyl-,(C₁-C₆)alkynl-, (C₁-C₆)alkoxy-, trihalo(C₁-C₆)alkyl- ,(C₁-C₆)alkylamino-, ((C₁-C₆)₂)dialkylamino-, amino-, cyano, and halo-;and (b) benzyloxy-, phenylsulfonyl-, phenylaminocarbonyl-,(C₁-C₉)heteroarylsulfonyl-, and (C₁-C₉)heteroarylaminocarbonyl-,optionally substituted by one or more groups selected from the groupconsisting of (C₁-C₆)alkyl-, (C₂-C₆)alkynyl-, trihalo(C₁-C₆)alkyl,(C₁-C₆)alkoxy-, (C₁-C₆)alkylamino-, ((C₁-C₆)₂)alkylamino-, and halo. 6.A compound according to claim 1 wherein one or more of substituents R³is selected from the groups consisting of (C₁-C₆)alkyl-,trihalo(C₁-C₆)alkyl-, deuterium, and fluorine.
 7. A compound accordingto claim 6 wherein R³ is trifluoromethyl.
 8. A compound selected fromthe group consisting of (a)1-[(2-anilino)-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline; (b)1-[2-[(4-bromophenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;(c)1-[2-[(4-methoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;(d)1-[2-[(1H-indazole-5-yl)]-4-pyrimidyl]-6-methyl-1,2,3,4-tetrahydroquinoline;(e)1-[2-[(4-phenoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;(f)1-[2-[(3,4-dimethoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;(g)1-[2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;(h)1-[2-[(4,N-phenylaminophenyl)amino]-4-pyrimidinyl]-6-methyl-1,2,3,4-tetrahydroquinoline;(i)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(6-morpholin-4-yl-pyridin-3-yl)-amine;(j)5-[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-1,3-dihydro-benzoimidazol-2-one;(k)(2,3-Dimethyl-1H-indol-5-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;(l)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(2-methyl-2H-pyrazol-3-yl)-amine;(m) (6-Methoxy-pyridin-3-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine; (n)(4-Fluoro-3-methyl-phenyl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;(o)(5-Cyclopropyl-2H-pyrazol-3-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;(p)4-Benzyl-N3-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-1H-pyrazole-3,5-diamine;(q)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(4-methyl-thiazol-2-yl)-amine;and (r)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(5-methyl-1H-pyrazol-3-yl)-amine.9. A compound selected from the group consisting of (a)[4-(3,4-Dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(6-pyrrolidin-1-yl-pyridin-3-yl)-amine;(b)(1-Cyclopentyl-1H-indol-6-yl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;(c)[4-(6-Methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-oxazol-4-yl-amine;(d)(3,4-Dichloro-phenyl)-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;and (e)[4-(3,4-Dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-isothiazol-3-yl-amine.10. A compound selected from the group consisting of (a)2-({5-[4-(2,3-Dihydro-benzo[1,4]oxazin-4-yl)-pyrimidin-2-ylamino]-pyridin-2-yl}-methyl-amino)-ethanol;(b)N-{5-[4-(3-Oxo-3,4-dihydro-2H-quinoxalin-1-yl)-pyrimidin-2-ylamino]-pyridin-2-yl}-acetamide;(c)3-Chloro-N-[4-(4-methyl-3-oxo-3,4-dihydro-2H-quinoxalin-1-yl)-pyrimidin-2-yl]-benzamide;(d)[4-(2,3-Dihydro-benzo[1,4]thiazin-4-yl)-pyrimidin-2-yl]-oxazol-4-yl-amine;(e)N-[4-(5-Fluoro-2,3-dihydro-indol-1-yl)-pyrimidin-2-yl]-3-methoxy-benzenesulfonamide;(f)[4-(5,6-Dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyrimidin-2-yl]-(2-trifluoromethyl-phenyl)-amine;(g)6-Methoxy-1-[2-(pyridazin-3-ylamino)-pyrimidin-4-yl]-2,3-dihydro-1H-quinolin-4-one;(h)2-{5-[4-(3,4-Dihydro-2H-quinoxalin-1-yl)-pyrimidin-2-ylamino]-indol-1-yl}-ethanol;(i)(2H-Pyrazol-3-yl)-[4-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine;(j)1-[4-(3,4-Dihydro-2H-[1,5]naphthyridin-1-yl)-pyrimidin-2-yl]-3-ethyl-urea;(k)1-[4-(2,3-Dihydro-benzo[1,4]oxazin-4-yl)-pyrimidin-2-yl]-3-(2-ethoxy-ethyl)-urea;(l) [4-(3,3-Dimethyl-2,3-dihydro-indol-1-yl)-pyrimidin-2-yl]-carbamicacid tert-butyl ester; (m)3-Cyano-N-[4-(7-methoxy-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-pyrimidin-2-yl]-benzamide;(n)Isoxazol-4-yl-[4-(2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-pyrimidin-2-yl]-amine;(o)(3,4-Dichloro-phenyl)-[4-(3,4-dihydro-2H-benzo[b][1,4]thiazepin-5-yl)-pyrimidin-2-yl]-amine;(p)(6-Aziridin-1-yl-pyridin-3-yl)-[4-(5-methanesulfonyl-2,3-dihydro-indol-1-yl)-pyrimidin-2-yl]-amine;(q)N²-Cyclopropyl-N⁵-[4-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-pyridine-2,5-diamine;and (r) Benzo[1,3]dioxole-5-carboxylic acid[4-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amide.
 11. Acompound according to claim 1, wherein X is methylene.
 12. A compoundaccording to claim 1, wherein the structural component thereof that isrepresented by

represents: 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine;2,3-Dihydro-1H-pyrrolo[2,3-c]pyridine;2,3-Dihydro-1H-pyrrolo[3,2-c]pyridine;2,3-Dihydro-1H-pyrrolo[3,2-b]pyridine;6,7-Dihydro-5H-pyrrolo[3,2-d]pyrimidine;6,7-Dihydro-5H-pyrrolo[3,2-d][1,2,3]triazine;6,7-Dihydro-5H-pyrrolo[2,3-d][1,2,3]triazine; 1,4,5,7-Tetraaza-indan;1,4,6,7-Tetraaza-indan; 6,7-Dihydro-5H-pyrrolo[2,3-c]pyridazine;2,3-Dihydro-1H-pyrrolo[2,3-d]pyridazine;6,7-Dihydro-5H-pyrrolo[3,2-c]pyridazine;6,7-Dihydro-5H-pyrrolo[2,3-b]pyrazine;6,7-Dihydro-5H-pyrimido[4,5-b][1,4]oxazine;5,6,7,8-Tetrahydro-pteridine; 1,2,3,4-Tetrahydro-pyrido[2,3-b]pyrazine;1,2,3,4-Tetrahydro-pyrido[3,4-b]pyrazine;1,2,3,4-Tetrahydro-pyrido[3,4-b]pyrazine;1,2,3,4-Tetrahydro-pyrido[2,3-b]pyrazine;5,6,7,8-Tetrahydro-pyrazino[2,3-c]pyridazine;5,6,7,8-Tetrahydro-pteridine;1,2,3,4-Tetrahydro-pyrazino[2,3-d]pyridazine;5,6,7,8-Tetrahydro-pyrazino[2,3-c]pyridazine;1,2,3,4-Tetrahydro-pyrazino[2,3-b]pyrazine;5,6,7,8-Tetrahydro-pyrazino[2,3-e][1,2,4]triazine;5,6,7,8-Tetrahydro-pyrazino[2,3-e][1,2,4]triazine;5,6,7,8-Tetrahydro-pyrazino[2,3-d][1,2,3]triazine;5,6,7,8-Tetrahydro-pyrazino[2,3-d][1,2,3]triazine;2,3-Dihydro-1H-4-oxa-1,5-diaza-naphthalene;2,3-Dihydro-1H-4-oxa-1,6-diaza-naphthalene;3,4-Dihydro-2H-1-oxa-4,6-diaza-naphthalene;3,4-Dihydro-2H-1-oxa-4,5-diaza-naphthalene;7,8-Dihydro-6H-5-oxa-1,2,8-triaza-naphthalene;3,4-Dihydro-2H-1-oxa-4,6,7-triaza-naphthalene;6,7-Dihydro-5H-8-oxa-1,2,5-triaza-naphthalene;3,4-Dihydro-2H-1-oxa-4,5,8-triaza-naphthalene;7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazine;6,7-Dihydro-5H-pyrimido[4,5-b][1,4]oxazine;6,7-Dihydro-5H-8-oxa-1,2,3,5-tetraaza-naphthalene;6,7-Dihydro-5H-8-oxa-1,2,4,5-tetraaza-naphthalene;7,8-Dihydro-6H-5-oxa-1,2,3,8-tetraaza-naphthalene;6,7-Dihydro-5H-8-oxa-1,2,4,5-tetraaza-naphthalene;2,3-Dihydro-1H-pyrido[2,3-b][1,4]thiazine;2,3-Dihydro-1H-4-thia-1,6-diaza-naphthalene;3,4-Dihydro-2H-1-thia-4,6-diaza-naphthalene;3,4-Dihydro-2H-pyrido[3,2-b][1,4]thiazine;7,8-Dihydro-6H-5-thia-1,2,8-triaza-naphthalene;3,4-Dihydro-2H-1-thia-4,6,7-triaza-naphthalene;6,7-Dihydro-5H-8-thia-1,2,5-triaza-naphthalene;6,7-Dihydro-5H-pyrimido[4,5-b][1,4]thiazine;7,8-Dihydro-6H-pyrimido[5,4-b][1,4]thiazine;3,4-Dihydro-2H-1-thia-4,5,8-triaza-naphthalene;6,7-Dihydro-5H-8-thia-1,2,4,5-tetraaza-naphthalene;7,8-Dihydro-6H-5-thia-1,2,4,8-tetraaza-naphthalene;7,8-Dihydro-6H-5-thia-1,2,3,8-tetraaza-naphthalene;6,7-Dihydro-5H-8-thia-1,2,3,5-tetraaza-naphthalene;5,6,7,8-Tetrahydro-pyrido[3,2-d]pyrimidine;1,2,3,4-Tetrahydro-pyrido[2,3-d]pyridazine;5,6,7,8-Tetrahydro-pyrido[2,3-b]pyrazine;5,6,7,8-Tetrahydro-pyrido[3,2-e][1,2,4]triazine;5,6,7,8-Tetrahydro-pyrido[2,3-e][1,2,4]triazine;5,6,7,8-Tetrahydro-pyrido[3,2-d][1,2,3]triazine; or5,6,7,8-Tetrahydro-pyrido(2,3-d][1,2,3]triazine.
 13. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 1, and a pharmaceutical carrier.